E2AK2_HUMAN
ID E2AK2_HUMAN Reviewed; 551 AA.
AC P19525; A8K3P0; D6W584; E9PC80; Q52M43; Q7Z6F6; Q9UIR4;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1991, sequence version 2.
DT 03-AUG-2022, entry version 243.
DE RecName: Full=Interferon-induced, double-stranded RNA-activated protein kinase;
DE EC=2.7.11.1;
DE AltName: Full=Eukaryotic translation initiation factor 2-alpha kinase 2;
DE Short=eIF-2A protein kinase 2;
DE AltName: Full=Interferon-inducible RNA-dependent protein kinase;
DE AltName: Full=P1/eIF-2A protein kinase;
DE AltName: Full=Protein kinase RNA-activated;
DE Short=PKR;
DE Short=Protein kinase R {ECO:0000303|PubMed:11438532};
DE AltName: Full=Tyrosine-protein kinase EIF2AK2;
DE EC=2.7.10.2;
DE AltName: Full=p68 kinase;
GN Name=EIF2AK2; Synonyms=PKR, PRKR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 101-118 AND
RP 309-325, AND INDUCTION.
RX PubMed=1695551; DOI=10.1016/0092-8674(90)90374-n;
RA Meurs E., Chong K., Galabru J., Thomas N.S.B., Kerr I.M., Williams B.R.G.,
RA Hovanessian A.G.;
RT "Molecular cloning and characterization of the human double-stranded RNA-
RT activated protein kinase induced by interferon.";
RL Cell 62:379-390(1990).
RN [2]
RP SEQUENCE REVISION.
RA Meurs E.;
RL Submitted (AUG-1990) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1373553; DOI=10.1016/0042-6822(92)90732-5;
RA Thomis D.C., Doohan J.P., Samuel C.E.;
RT "Mechanism of interferon action: cDNA structure, expression, and regulation
RT of the interferon-induced, RNA-dependent P1/eIF-2 alpha protein kinase from
RT human cells.";
RL Virology 188:33-46(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RX PubMed=8921913; DOI=10.1016/0378-1119(96)00314-9;
RA Kuhen K.L., Shen X., Samuel C.E.;
RT "Mechanism of interferon action sequence of the human interferon-inducible
RT RNA-dependent protein kinase (PKR) deduced from genomic clones.";
RL Gene 178:191-193(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=8812437; DOI=10.1006/geno.1996.0446;
RA Kuhen K.L., Shen X., Carlisle E.R., Richardson A.L., Weier H.-U.G.,
RA Tanaka H., Samuel C.E.;
RT "Structural organization of the human gene (PKR) encoding an interferon-
RT inducible RNA-dependent protein kinase (PKR) and differences from its mouse
RT homolog.";
RL Genomics 36:197-201(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9726442; DOI=10.1089/jir.1998.18.609;
RA Xu Z., Williams B.R.;
RT "Genomic features of human PKR: alternative splicing and a polymorphic CGG
RT repeat in the 5'-untranslated region.";
RL J. Interferon Cytokine Res. 18:609-616(1998).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Li H., Huang F., Shen C., Zhou G., Zheng G., Ke R., Lin L., Yang S.;
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Embryo;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [13]
RP PROTEIN SEQUENCE OF 2-18; 27-40; 70-77; 414-426 AND 430-440, CLEAVAGE OF
RP INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RC TISSUE=Prostatic carcinoma;
RA Bienvenut W.V., Gao M., Leug H.;
RL Submitted (JUN-2009) to UniProtKB.
RN [14]
RP INTERACTION WITH DNAJC3.
RX PubMed=8576172; DOI=10.1074/jbc.271.3.1702;
RA Polyak S.J., Tang N., Wambach M., Barber G.N., Katze M.G.;
RT "The P58 cellular inhibitor complexes with the interferon-induced, double-
RT stranded RNA-dependent protein kinase, PKR, to regulate its
RT autophosphorylation and activity.";
RL J. Biol. Chem. 271:1702-1707(1996).
RN [15]
RP INTERACTION WITH HIV-1 TAT.
RX PubMed=9079663; DOI=10.1074/jbc.272.13.8388;
RA Brand S.R., Kobayashi R., Mathews M.B.;
RT "The Tat protein of human immunodeficiency virus type 1 is a substrate and
RT inhibitor of the interferon-induced, virally activated protein kinase,
RT PKR.";
RL J. Biol. Chem. 272:8388-8395(1997).
RN [16]
RP INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION).
RX PubMed=9143277; DOI=10.1006/viro.1997.8493;
RA Gale M.J. Jr., Korth M.J., Tang N.M., Tan S.-L., Hopkins D.A., Dever T.E.,
RA Polyak S.J., Gretch D.R., Katze M.G.;
RT "Evidence that hepatitis C virus resistance to interferon is mediated
RT through repression of the PKR protein kinase by the nonstructural 5A
RT protein.";
RL Virology 230:217-227(1997).
RN [17]
RP INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION).
RX PubMed=9710605; DOI=10.1128/mcb.18.9.5208;
RA Gale M.J. Jr., Blakely C.M., Kwieciszewski B., Tan S.-L., Dossett M.,
RA Tang N.M., Korth M.J., Polyak S.J., Gretch D.R., Katze M.G.;
RT "Control of PKR protein kinase by hepatitis C virus nonstructural 5A
RT protein: molecular mechanisms of kinase regulation.";
RL Mol. Cell. Biol. 18:5208-5218(1998).
RN [18]
RP INTERACTION WITH INFLUENZA A NS1 PROTEIN.
RX PubMed=9781815; DOI=10.1089/jir.1998.18.757;
RA Tan S.L., Katze M.G.;
RT "Biochemical and genetic evidence for complex formation between the
RT influenza A virus NS1 protein and the interferon-induced PKR protein
RT kinase.";
RL J. Interferon Cytokine Res. 18:757-766(1998).
RN [19]
RP INTERACTION WITH HCV ENVELOPE GLYCOPROTEIN E2 (MICROBIAL INFECTION).
RX PubMed=10390359; DOI=10.1126/science.285.5424.107;
RA Taylor D.R., Shi S.T., Romano P.R., Barber G.N., Lai M.M.C.;
RT "Inhibition of the interferon-inducible protein kinase PKR by HCV E2
RT protein.";
RL Science 285:107-110(1999).
RN [20]
RP FUNCTION, AND INTERACTION WITH IKBKB.
RX PubMed=10848580; DOI=10.1128/mcb.20.13.4532-4542.2000;
RA Bonnet M.C., Weil R., Dam E., Hovanessian A.G., Meurs E.F.;
RT "PKR stimulates NF-kappaB irrespective of its kinase function by
RT interacting with the IkappaB kinase complex.";
RL Mol. Cell. Biol. 20:4532-4542(2000).
RN [21]
RP INTERACTION WITH TARBP2.
RX PubMed=11438532; DOI=10.1074/jbc.m103584200;
RA Daher A., Longuet M., Dorin D., Bois F., Segeral E., Bannwarth S.,
RA Battisti P.-L., Purcell D.F., Benarous R., Vaquero C., Meurs E.F.,
RA Gatignol A.;
RT "Two dimerization domains in the trans-activation response RNA-binding
RT protein (TRBP) individually reverse the protein kinase R inhibition of HIV-
RT 1 long terminal repeat expression.";
RL J. Biol. Chem. 276:33899-33905(2001).
RN [22]
RP PHOSPHORYLATION AT SER-83; THR-88; THR-89; THR-90; SER-242; THR-255 AND
RP THR-258, MUTAGENESIS OF SER-83; THR-88; THR-89; THR-90; SER-242; THR-255;
RP THR-258 AND LYS-296, AND INHIBITION BY HCV E2 ENVELOPE PROTEIN.
RX PubMed=11152499; DOI=10.1128/jvi.75.3.1265-1273.2001;
RA Taylor D.R., Tian B., Romano P.R., Hinnebusch A.G., Lai M.M.C.,
RA Mathews M.B.;
RT "Hepatitis C virus envelope protein E2 does not inhibit PKR by simple
RT competition with autophosphorylation sites in the RNA-binding domain.";
RL J. Virol. 75:1265-1273(2001).
RN [23]
RP MUTAGENESIS, AND PHOSPHORYLATION AT THR-446 AND THR-451.
RX PubMed=11337501; DOI=10.1074/jbc.m102108200;
RA Zhang F., Romano P.R., Nagamura-Inoue T., Tian B., Dever T.E.,
RA Mathews M.B., Ozato K., Hinnebusch A.G.;
RT "Binding of double-stranded RNA to protein kinase PKR is required for
RT dimerization and promotes critical autophosphorylation events in the
RT activation loop.";
RL J. Biol. Chem. 276:24946-24958(2001).
RN [24]
RP INTERACTION WITH HHV-8 PROTEIN VIRF2 (MICROBIAL INFECTION).
RX PubMed=11160738; DOI=10.1128/jvi.75.5.2345-2352.2001;
RA Burysek L., Pitha P.M.;
RT "Latently expressed human herpesvirus 8-encoded interferon regulatory
RT factor 2 inhibits double-stranded RNA-activated protein kinase.";
RL J. Virol. 75:2345-2352(2001).
RN [25]
RP FUNCTION, AND INTERACTION WITH HHV-1 US11 (MICROBIAL INFECTION).
RX PubMed=11836380; DOI=10.1128/jvi.76.5.2029-2035.2002;
RA Cassady K.A., Gross M.;
RT "The herpes simplex virus type 1 U(S)11 protein interacts with protein
RT kinase R in infected cells and requires a 30-amino-acid sequence adjacent
RT to a kinase substrate domain.";
RL J. Virol. 76:2029-2035(2002).
RN [26]
RP INTERACTION WITH NPM1, AND ACTIVITY REGULATION.
RX PubMed=12882984; DOI=10.1074/jbc.m301392200;
RA Pang Q., Christianson T.A., Koretsky T., Carlson H., David L., Keeble W.,
RA Faulkner G.R., Speckhart A., Bagby G.C.;
RT "Nucleophosmin interacts with and inhibits the catalytic function of
RT eukaryotic initiation factor 2 kinase PKR.";
RL J. Biol. Chem. 278:41709-41717(2003).
RN [27]
RP FUNCTION, AND INTERACTION WITH MAP2K6.
RX PubMed=15229216; DOI=10.1074/jbc.m406554200;
RA Silva A.M., Whitmore M., Xu Z., Jiang Z., Li X., Williams B.R.;
RT "Protein kinase R (PKR) interacts with and activates mitogen-activated
RT protein kinase kinase 6 (MKK6) in response to double-stranded RNA
RT stimulation.";
RL J. Biol. Chem. 279:37670-37676(2004).
RN [28]
RP IDENTIFICATION IN A COMPLEX WITH FANCA; FANCC; FANCG AND HSP70.
RX PubMed=15299030; DOI=10.1074/jbc.m403884200;
RA Zhang X., Li J., Sejas D.P., Rathbun K.R., Bagby G.C., Pang Q.;
RT "The Fanconi anemia proteins functionally interact with the protein kinase
RT regulated by RNA (PKR).";
RL J. Biol. Chem. 279:43910-43919(2004).
RN [29]
RP FUNCTION, INTERACTION WITH TRAF2; TRAF5 AND TRAF6, AND SUBCELLULAR
RP LOCATION.
RX PubMed=15121867; DOI=10.1128/mcb.24.10.4502-4512.2004;
RA Gil J., Garcia M.A., Gomez-Puertas P., Guerra S., Rullas J., Nakano H.,
RA Alcami J., Esteban M.;
RT "TRAF family proteins link PKR with NF-kappa B activation.";
RL Mol. Cell. Biol. 24:4502-4512(2004).
RN [30]
RP INHIBITION BY VACCINIA VIRUS PROTEIN E3.
RX PubMed=15207627; DOI=10.1016/j.virol.2004.03.012;
RA Langland J.O., Jacobs B.L.;
RT "Inhibition of PKR by vaccinia virus: role of the N- and C-terminal domains
RT of E3L.";
RL Virology 324:419-429(2004).
RN [31]
RP REVIEW.
RX PubMed=17158706; DOI=10.1128/mmbr.00027-06;
RA Garcia M.A., Gil J., Ventoso I., Guerra S., Domingo E., Rivas C.,
RA Esteban M.;
RT "Impact of protein kinase PKR in cell biology: from antiviral to
RT antiproliferative action.";
RL Microbiol. Mol. Biol. Rev. 70:1032-1060(2006).
RN [32]
RP PHOSPHORYLATION AT TYR-101; TYR-162 AND TYR-293.
RX PubMed=16373505; DOI=10.1073/pnas.0508207103;
RA Su Q., Wang S., Baltzis D., Qu L.K., Wong A.H., Koromilas A.E.;
RT "Tyrosine phosphorylation acts as a molecular switch to full-scale
RT activation of the eIF2alpha RNA-dependent protein kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:63-68(2006).
RN [33]
RP INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION).
RX PubMed=16951545;
RA Liang Y., Kang C.B., Yoon H.S.;
RT "Molecular and structural characterization of the domain 2 of hepatitis C
RT virus non-structural protein 5A.";
RL Mol. Cells 22:13-20(2006).
RN [34]
RP INTERACTION WITH HCV NON-STRUCTURAL PROTEIN 5A (MICROBIAL INFECTION).
RX PubMed=17451199; DOI=10.3748/wjg.v13.i8.1195;
RA Veillon P., Payan C., Le Guillou-Guillemette H., Gaudy C., Lunel F.;
RT "Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b
RT during interferon or combined interferon-ribavirin therapy.";
RL World J. Gastroenterol. 13:1195-1203(2007).
RN [35]
RP INTERACTION WITH HCV MATURE CORE PROTEIN (MICROBIAL INFECTION).
RX PubMed=17267064; DOI=10.1016/j.virusres.2006.12.010;
RA Yan X.B., Battaglia S., Boucreux D., Chen Z., Brechot C., Pavio N.;
RT "Mapping of the interacting domains of hepatitis C virus core protein and
RT the double-stranded RNA-activated protein kinase PKR.";
RL Virus Res. 125:79-87(2007).
RN [36]
RP INTERACTION WITH ADAR.
RX PubMed=17079286; DOI=10.1128/jvi.01527-06;
RA Nie Y., Hammond G.L., Yang J.H.;
RT "Double-stranded RNA deaminase ADAR1 increases host susceptibility to virus
RT infection.";
RL J. Virol. 81:917-923(2007).
RN [37]
RP REVIEW ON ACTIVITY REGULATION.
RX PubMed=17196820; DOI=10.1016/j.tibs.2006.12.003;
RA Cole J.L.;
RT "Activation of PKR: an open and shut case?";
RL Trends Biochem. Sci. 32:57-62(2007).
RN [38]
RP FUNCTION, INTERACTION WITH NCK1, AND ACTIVITY REGULATION.
RX PubMed=18835251; DOI=10.1016/j.bbrc.2008.09.112;
RA Cardin E., Larose L.;
RT "Nck-1 interacts with PKR and modulates its activation by dsRNA.";
RL Biochem. Biophys. Res. Commun. 377:231-235(2008).
RN [39]
RP INTERACTION WITH DUS2L, AND ACTIVITY REGULATION.
RX PubMed=18096616; DOI=10.1093/nar/gkm1129;
RA Mittelstadt M., Frump A., Khuu T., Fowlkes V., Handy I., Patel C.V.,
RA Patel R.C.;
RT "Interaction of human tRNA-dihydrouridine synthase-2 with interferon-
RT induced protein kinase PKR.";
RL Nucleic Acids Res. 36:998-1008(2008).
RN [40]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83 AND SER-456, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [41]
RP FUNCTION.
RX PubMed=19507191; DOI=10.1002/jcp.21848;
RA Blalock W.L., Grimaldi C., Fala F., Follo M., Horn S., Basecke J.,
RA Martinelli G., Cocco L., Martelli A.M.;
RT "PKR activity is required for acute leukemic cell maintenance and growth: a
RT role for PKR-mediated phosphatase activity to regulate GSK-3
RT phosphorylation.";
RL J. Cell. Physiol. 221:232-241(2009).
RN [42]
RP FUNCTION, AND INTERACTION WITH DHX9.
RX PubMed=19229320; DOI=10.1371/journal.ppat.1000311;
RA Sadler A.J., Latchoumanin O., Hawkes D., Mak J., Williams B.R.;
RT "An antiviral response directed by PKR phosphorylation of the RNA helicase
RT A.";
RL PLoS Pathog. 5:E1000311-E1000311(2009).
RN [43]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [44]
RP FUNCTION IN HCV RESTRICTION.
RX PubMed=19189853; DOI=10.1016/j.virusres.2009.01.007;
RA Kang J.I., Kwon S.N., Park S.H., Kim Y.K., Choi S.Y., Kim J.P., Ahn B.Y.;
RT "PKR protein kinase is activated by hepatitis C virus and inhibits viral
RT replication through translational control.";
RL Virus Res. 142:51-56(2009).
RN [45]
RP FUNCTION.
RX PubMed=20171114; DOI=10.1016/j.cyto.2010.01.008;
RA Lin S.S., Lee D.C., Law A.H., Fang J.W., Chua D.T., Lau A.S.;
RT "A role for protein kinase PKR in the mediation of Epstein-Barr virus
RT latent membrane protein-1-induced IL-6 and IL-10 expression.";
RL Cytokine 50:210-219(2010).
RN [46]
RP FUNCTION AS CDK1 KINASE UPON DNA DAMAGE, AND FUNCTION AS TYROSINE-PROTEIN
RP KINASE.
RX PubMed=20395957; DOI=10.1038/embor.2010.45;
RA Yoon C.-H., Miah M.A., Kim K.P., Bae Y.-S.;
RT "New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers
RT Cdc2 polyubiquitination and G2 arrest under genotoxic stresses.";
RL EMBO Rep. 11:393-399(2010).
RN [47]
RP FUNCTION.
RX PubMed=21123651; DOI=10.1101/gad.1965010;
RA Harashima A., Guettouche T., Barber G.N.;
RT "Phosphorylation of the NFAR proteins by the dsRNA-dependent protein kinase
RT PKR constitutes a novel mechanism of translational regulation and cellular
RT defense.";
RL Genes Dev. 24:2640-2653(2010).
RN [48]
RP INTERACTION WITH HRSV NUCLEOPROTEIN (MICROBIAL INFECTION).
RX PubMed=20519500; DOI=10.1074/jbc.m109.077321;
RA Groskreutz D.J., Babor E.C., Monick M.M., Varga S.M., Hunninghake G.W.;
RT "Respiratory syncytial virus limits alpha subunit of eukaryotic translation
RT initiation factor 2 (eIF2alpha) phosphorylation to maintain translation and
RT viral replication.";
RL J. Biol. Chem. 285:24023-24031(2010).
RN [49]
RP FUNCTION IN HCV RESTRICTION.
RX PubMed=19840259; DOI=10.1111/j.1478-3231.2009.02144.x;
RA Chang J.H., Kato N., Muroyama R., Taniguchi H., Guleng B., Dharel N.,
RA Shao R.X., Tateishi K., Jazag A., Kawabe T., Omata M.;
RT "Double-stranded RNA-activated protein kinase inhibits hepatitis C virus
RT replication but may be not essential in interferon treatment.";
RL Liver Int. 30:311-318(2010).
RN [50]
RP FUNCTION, AND PHOSPHORYLATION AT THR-451.
RX PubMed=20685959; DOI=10.1091/mbc.e10-06-0481;
RA Yang X., Nath A., Opperman M.J., Chan C.;
RT "The double-stranded RNA-dependent protein kinase differentially regulates
RT insulin receptor substrates 1 and 2 in HepG2 cells.";
RL Mol. Biol. Cell 21:3449-3458(2010).
RN [51]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [52]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [53]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION.
RX PubMed=21029237; DOI=10.1111/j.1750-3639.2010.00437.x;
RA Bose A., Mouton-Liger F., Paquet C., Mazot P., Vigny M., Gray F., Hugon J.;
RT "Modulation of tau phosphorylation by the kinase PKR: implications in
RT Alzheimer's disease.";
RL Brain Pathol. 21:189-200(2011).
RN [54]
RP REVIEW.
RX PubMed=21924887; DOI=10.1016/j.coi.2011.08.009;
RA Pfaller C.K., Li Z., George C.X., Samuel C.E.;
RT "Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old
RT players as modulators of the interferon response.";
RL Curr. Opin. Immunol. 23:573-582(2011).
RN [55]
RP REVIEW.
RX PubMed=21166592; DOI=10.1089/jir.2010.0099;
RA Pindel A., Sadler A.;
RT "The role of protein kinase R in the interferon response.";
RL J. Interferon Cytokine Res. 31:59-70(2011).
RN [56]
RP FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY, AND
RP PHOSPHORYLATION.
RX PubMed=21072047; DOI=10.1038/leu.2010.264;
RA Blalock W.L., Bavelloni A., Piazzi M., Tagliavini F., Faenza I.,
RA Martelli A.M., Follo M.Y., Cocco L.;
RT "Multiple forms of PKR present in the nuclei of acute leukemia cells
RT represent an active kinase that is responsive to stress.";
RL Leukemia 25:236-245(2011).
RN [57]
RP FUNCTION IN HBV RESTRICTION.
RX PubMed=21710204; DOI=10.1007/s10059-011-1059-6;
RA Park I.H., Baek K.W., Cho E.Y., Ahn B.Y.;
RT "PKR-dependent mechanisms of interferon-? for inhibiting hepatitis B virus
RT replication.";
RL Mol. Cells 32:167-172(2011).
RN [58]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=22214662; DOI=10.4161/cc.11.2.18999;
RA Bennett R.L., Pan Y., Christian J., Hui T., May W.S. Jr.;
RT "The RAX/PACT-PKR stress response pathway promotes p53 sumoylation and
RT activation, leading to G(1) arrest.";
RL Cell Cycle 11:407-417(2012).
RN [59]
RP REVIEW.
RX PubMed=22633454; DOI=10.1016/j.immuni.2012.05.010;
RA Lacy-Hulbert A., Stuart L.M.;
RT "Penetration resistance: PKR's other talent.";
RL Immunity 36:695-696(2012).
RN [60]
RP FUNCTION.
RX PubMed=22948139; DOI=10.1074/jbc.m112.390039;
RA McAllister C.S., Taghavi N., Samuel C.E.;
RT "Protein kinase PKR amplification of interferon beta induction occurs
RT through initiation factor eIF-2alpha-mediated translational control.";
RL J. Biol. Chem. 287:36384-36392(2012).
RN [61]
RP FUNCTION, AND INTERACTION WITH STAT3.
RX PubMed=23084476; DOI=10.1016/j.molcel.2012.09.013;
RA Shen S., Niso-Santano M., Adjemian S., Takehara T., Malik S.A., Minoux H.,
RA Souquere S., Marino G., Lachkar S., Senovilla L., Galluzzi L., Kepp O.,
RA Pierron G., Maiuri M.C., Hikita H., Kroemer R., Kroemer G.;
RT "Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity.";
RL Mol. Cell 48:667-680(2012).
RN [62]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [63]
RP FUNCTION, INTERACTION WITH NLRP1; NLRP3; NLRC4 AND AIM2, AND
RP AUTOPHOSPHORYLATION.
RX PubMed=22801494; DOI=10.1038/nature11290;
RA Lu B., Nakamura T., Inouye K., Li J., Tang Y., Lundbaeck P.,
RA Valdes-Ferrer S.I., Olofsson P.S., Kalb T., Roth J., Zou Y.,
RA Erlandsson-Harris H., Yang H., Ting J.P., Wang H., Andersson U.,
RA Antoine D.J., Chavan S.S., Hotamisligil G.S., Tracey K.J.;
RT "Novel role of PKR in inflammasome activation and HMGB1 release.";
RL Nature 488:670-674(2012).
RN [64]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [65]
RP REVIEW.
RX PubMed=23092889; DOI=10.1126/scisignal.2003511;
RA Kang R., Tang D.;
RT "PKR-dependent inflammatory signals.";
RL Sci. Signal. 5:PE47-PE47(2012).
RN [66]
RP FUNCTION.
RX PubMed=22381929; DOI=10.1016/j.virol.2012.01.029;
RA Taghavi N., Samuel C.E.;
RT "Protein kinase PKR catalytic activity is required for the PKR-dependent
RT activation of mitogen-activated protein kinases and amplification of
RT interferon beta induction following virus infection.";
RL Virology 427:208-216(2012).
RN [67]
RP REVIEW.
RX PubMed=23202496; DOI=10.3390/v4112598;
RA Dabo S., Meurs E.F.;
RT "dsRNA-dependent protein kinase PKR and its role in stress, signaling and
RT HCV infection.";
RL Viruses 4:2598-2635(2012).
RN [68]
RP TISSUE SPECIFICITY.
RX PubMed=23403623; DOI=10.1182/blood-2012-09-456400;
RA Liu X., Bennett R.L., Cheng X., Byrne M., Reinhard M.K., May W.S. Jr.;
RT "PKR regulates proliferation, differentiation and survival of murine
RT hematopoietic stem/progenitor cells.";
RL Blood 121:3364-3374(2013).
RN [69]
RP REVIEW.
RX PubMed=23354059; DOI=10.1007/s00018-012-1252-6;
RA Donnelly N., Gorman A.M., Gupta S., Samali A.;
RT "The eIF2alpha kinases: their structures and functions.";
RL Cell. Mol. Life Sci. 70:3493-3511(2013).
RN [70]
RP FUNCTION, ISGYLATION AT LYS-69 AND LYS-159, AND ACTIVITY REGULATION.
RX PubMed=23229543; DOI=10.1074/jbc.m112.401851;
RA Okumura F., Okumura A.J., Uematsu K., Hatakeyama S., Zhang D.E., Kamura T.;
RT "Activation of double-stranded RNA-activated protein kinase (PKR) by
RT interferon-stimulated gene 15 (ISG15) modification down-regulates protein
RT translation.";
RL J. Biol. Chem. 288:2839-2847(2013).
RN [71]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-542, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [72]
RP INTERACTION WITH TOSCANA VIRUS PROTEIN NSS (MICROBIAL INFECTION), AND
RP ACTIVITY REGULATION.
RX PubMed=23325696; DOI=10.1128/jvi.02506-12;
RA Kalveram B., Ikegami T.;
RT "Toscana virus NSs protein promoftes degradation of double-stranded RNA-
RT dependent protein kinase.";
RL J. Virol. 87:3710-3718(2013).
RN [73]
RP FUNCTION IN MV RESTRICTION.
RX PubMed=23115276; DOI=10.1128/jvi.02270-12;
RA Okonski K.M., Samuel C.E.;
RT "Stress granule formation induced by measles virus is protein kinase PKR
RT dependent and impaired by RNA adenosine deaminase ADAR1.";
RL J. Virol. 87:756-766(2013).
RN [74]
RP FUNCTION.
RX PubMed=23372823; DOI=10.1371/journal.pone.0055108;
RA Li Y., Xie J., Wu S., Xia J., Zhang P., Liu C., Zhang P., Huang X.;
RT "Protein kinase regulated by dsRNA downregulates the interferon production
RT in dengue virus- and dsrna-stimulated human lung epithelial cells.";
RL PLoS ONE 8:E55108-E55108(2013).
RN [75]
RP FUNCTION IN HCV RESTRICTION.
RX PubMed=23399035; DOI=10.1016/j.virol.2013.01.015;
RA Zhang L., Alter H.J., Wang H., Jia S., Wang E., Marincola F.M., Shih J.W.,
RA Wang R.Y.;
RT "The modulation of hepatitis C virus 1a replication by PKR is dependent on
RT NF-kB mediated interferon beta response in Huh7.5.1 cells.";
RL Virology 438:28-36(2013).
RN [76]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [77]
RP INTERACTION WITH VACCINIA VIRUS PROTEIN E3 (MICROBIAL INFECTION).
RX PubMed=25740987; DOI=10.1128/jvi.03288-14;
RA Dueck K.J., Hu Y.S., Chen P., Deschambault Y., Lee J., Varga J., Cao J.;
RT "Mutational analysis of vaccinia virus E3 protein: the biological functions
RT do not correlate with its biochemical capacity to bind double-stranded
RT RNA.";
RL J. Virol. 89:5382-5394(2015).
RN [78]
RP STRUCTURE BY NMR OF 1-175.
RX PubMed=9736623; DOI=10.1093/emboj/17.18.5458;
RA Nanduri S., Carpick B.W., Yang Y., Williams B.R.G., Qin J.;
RT "Structure of the double-stranded RNA-binding domain of the protein kinase
RT PKR reveals the molecular basis of its dsRNA-mediated activation.";
RL EMBO J. 17:5458-5465(1998).
RN [79]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 258-550 IN COMPLEX WITH EIF2ALPHA,
RP AND PHOSPHORYLATION AT THR-446.
RX PubMed=16179258; DOI=10.1016/j.cell.2005.06.044;
RA Dar A.C., Dever T.E., Sicheri F.;
RT "Higher-order substrate recognition of eIF2alpha by the RNA-dependent
RT protein kinase PKR.";
RL Cell 122:887-900(2005).
RN [80]
RP INVOLVEMENT IN LEUDEN, FUNCTION, VARIANTS LEUDEN LEU-11; SER-32; PHE-97;
RP SER-109; VAL-109; PHE-133; SER-325 AND CYS-461, CHARACTERIZATION OF
RP VARIANTS LEUDEN LEU-11; PHE-133 AND CYS-461, AND VARIANT GLN-114.
RX PubMed=32197074; DOI=10.1016/j.ajhg.2020.02.016;
RG Undiagnosed Diseases Network;
RA Mao D., Reuter C.M., Ruzhnikov M.R.Z., Beck A.E., Farrow E.G., Emrick L.T.,
RA Rosenfeld J.A., Mackenzie K.M., Robak L., Wheeler M.T., Burrage L.C.,
RA Jain M., Liu P., Calame D., Kuery S., Sillesen M., Schmitz-Abe K.,
RA Tonduti D., Spaccini L., Iascone M., Genetti C.A., Koenig M.K., Graf M.,
RA Tran A., Alejandro M., Lee B.H., Thiffault I., Agrawal P.B.,
RA Bernstein J.A., Bellen H.J., Chao H.T.;
RT "De novo EIF2AK1 and EIF2AK2 variants are associated with developmental
RT delay, leukoencephalopathy, and neurologic decompensation.";
RL Am. J. Hum. Genet. 106:570-583(2020).
RN [81]
RP VARIANTS [LARGE SCALE ANALYSIS] GLU-428; VAL-439 AND VAL-506.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: IFN-induced dsRNA-dependent serine/threonine-protein kinase
CC that phosphorylates the alpha subunit of eukaryotic translation
CC initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the
CC innate immune response to viral infection (PubMed:18835251,
CC PubMed:19507191, PubMed:19189853, PubMed:21123651, PubMed:21072047,
CC PubMed:22948139, PubMed:23229543, PubMed:22381929). Inhibits viral
CC replication via the integrated stress response (ISR): EIF2S1/eIF-2-
CC alpha phosphorylation in response to viral infection converts
CC EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting
CC to a shutdown of cellular and viral protein synthesis, while
CC concomitantly initiating the preferential translation of ISR-specific
CC mRNAs, such as the transcriptional activator ATF4 (PubMed:19189853,
CC PubMed:21123651, PubMed:22948139, PubMed:23229543). Exerts its
CC antiviral activity on a wide range of DNA and RNA viruses including
CC hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV)
CC and herpes simplex virus 1 (HHV-1) (PubMed:11836380, PubMed:19189853,
CC PubMed:20171114, PubMed:19840259, PubMed:21710204, PubMed:23115276,
CC PubMed:23399035). Also involved in the regulation of signal
CC transduction, apoptosis, cell proliferation and differentiation:
CC phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9,
CC ILF3, IRS1 and the HHV-1 viral protein US11 (PubMed:11836380,
CC PubMed:22214662, PubMed:19229320). In addition to serine/threonine-
CC protein kinase activity, also has tyrosine-protein kinase activity and
CC phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its
CC ubiquitination and proteosomal degradation (PubMed:20395957). Either as
CC an adapter protein and/or via its kinase activity, can regulate various
CC signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling
CC pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3)
CC involved in the expression of genes encoding pro-inflammatory cytokines
CC and IFNs (PubMed:22948139, PubMed:23084476, PubMed:23372823). Activates
CC the NF-kappa-B pathway via interaction with IKBKB and TRAF family of
CC proteins and activates the p38 MAP kinase pathway via interaction with
CC MAP2K6 (PubMed:10848580, PubMed:15121867, PubMed:15229216). Can act as
CC both a positive and negative regulator of the insulin signaling pathway
CC (ISP) (PubMed:20685959). Negatively regulates ISP by inducing the
CC inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at
CC 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A
CC which activates FOXO1, which in turn up-regulates the expression of
CC insulin receptor substrate 2 (IRS2) (PubMed:20685959). Can regulate
CC NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2
CC and NLRC4 inflammasomes (PubMed:22801494). Plays a role in the
CC regulation of the cytoskeleton by binding to gelsolin (GSN),
CC sequestering the protein in an inactive conformation away from actin
CC (By similarity). {ECO:0000250|UniProtKB:Q03963,
CC ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11836380,
CC ECO:0000269|PubMed:15121867, ECO:0000269|PubMed:15229216,
CC ECO:0000269|PubMed:18835251, ECO:0000269|PubMed:19189853,
CC ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19507191,
CC ECO:0000269|PubMed:19840259, ECO:0000269|PubMed:20171114,
CC ECO:0000269|PubMed:20395957, ECO:0000269|PubMed:20685959,
CC ECO:0000269|PubMed:21072047, ECO:0000269|PubMed:21123651,
CC ECO:0000269|PubMed:21710204, ECO:0000269|PubMed:22214662,
CC ECO:0000269|PubMed:22381929, ECO:0000269|PubMed:22801494,
CC ECO:0000269|PubMed:22948139, ECO:0000269|PubMed:23084476,
CC ECO:0000269|PubMed:23115276, ECO:0000269|PubMed:23229543,
CC ECO:0000269|PubMed:23372823, ECO:0000269|PubMed:23399035,
CC ECO:0000269|PubMed:32197074}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10027};
CC -!- ACTIVITY REGULATION: Initially produced in an inactive form and is
CC activated by binding to viral dsRNA, which causes dimerization and
CC autophosphorylation in the activation loop and stimulation of function.
CC ISGylation can activate it in the absence of viral infection. Can also
CC be activated by heparin, pro-inflammatory stimuli, growth factors,
CC cytokines, oxidative stress and the cellular protein PRKRA. Activity is
CC markedly stimulated by manganese ions. Activation is blocked by the
CC viral components HIV-1 Tat protein and large amounts of HIV-1 trans-
CC activation response (TAR) RNA element as well as by the cellular
CC proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana
CC virus (TOS) and Rift valley fever virus (RVFV) NSS which promote its
CC proteasomal degradation. Inhibited by vaccinia virus protein E3,
CC probably via dsRNA sequestering. {ECO:0000269|PubMed:12882984,
CC ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18835251,
CC ECO:0000269|PubMed:23229543, ECO:0000269|PubMed:23325696}.
CC -!- SUBUNIT: Homodimer. Interacts with STRBP (By similarity). Interacts
CC with DNAJC3. Forms a complex with FANCA, FANCC, FANCG and HSP70.
CC Interacts with ADAR/ADAR1. Interacts with IRS1 (By similarity). The
CC inactive form interacts with NCK1 and GSN. Interacts (via the kinase
CC catalytic domain) with STAT3 (via SH2 domain), TRAF2 (C-terminus),
CC TRAF5 (C-terminus) and TRAF6 (C-terminus). Interacts with MAP2K6,
CC IKBKB/IKKB, NPM1, TARBP2, NLRP1, NLRP3, NLRC4 and AIM2. Interacts (via
CC DRBM 1 domain) with DUS2L (via DRBM domain). Interacts with DHX9 (via
CC N-terminus) and this interaction is dependent upon activation of the
CC kinase. {ECO:0000250|UniProtKB:Q03963, ECO:0000269|PubMed:10390359,
CC ECO:0000269|PubMed:10848580, ECO:0000269|PubMed:11438532,
CC ECO:0000269|PubMed:12882984, ECO:0000269|PubMed:15121867,
CC ECO:0000269|PubMed:15229216, ECO:0000269|PubMed:15299030,
CC ECO:0000269|PubMed:16179258, ECO:0000269|PubMed:17079286,
CC ECO:0000269|PubMed:18096616, ECO:0000269|PubMed:18835251,
CC ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:22801494,
CC ECO:0000269|PubMed:23084476, ECO:0000269|PubMed:25740987,
CC ECO:0000269|PubMed:8576172, ECO:0000269|PubMed:9079663,
CC ECO:0000269|PubMed:9143277, ECO:0000269|PubMed:9781815}.
CC -!- SUBUNIT: (Microbial infection) Interacts with human herpes simplex
CC virus 1 (HHV-1) protein US11 in an RNA-dependent manner.
CC {ECO:0000269|PubMed:11836380}.
CC -!- SUBUNIT: (Microbial infection) The inactive form interacts with Toscana
CC virus (TOS) NSS. {ECO:0000269|PubMed:23325696}.
CC -!- SUBUNIT: (Microbial infection) Interacts with herpes virus 8 protein v-
CC IRF2; this interaction inhibits EIF2AK2 activation.
CC {ECO:0000269|PubMed:11160738}.
CC -!- SUBUNIT: (Microbial infection) Interacts with vaccinia protein E3.
CC {ECO:0000269|PubMed:25740987}.
CC -!- SUBUNIT: (Microbial infection) Interacts (via N-terminus) with
CC Hepatitis C virus (HCV) mature core protein (via N-terminus); this
CC interaction induces the autophosphorylation of EIF2AK2.
CC {ECO:0000269|PubMed:17267064}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Hepatitis C virus (HCV)
CC non-structural protein 5A (NS5A); this interaction leads to disruption
CC of EIF2AK2 dimerization by NS5A. {ECO:0000269|PubMed:16951545,
CC ECO:0000269|PubMed:17451199, ECO:0000269|PubMed:9143277,
CC ECO:0000269|PubMed:9710605}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Hepatitis C virus (HCV)
CC envelope glycoprotein E2; this interaction inhibits EIF2AK2 and blocks
CC its inhibitory effect on protein synthesis and cell growth.
CC {ECO:0000269|PubMed:9143277}.
CC -!- SUBUNIT: (Microbial infection) Interacts with human respiratory
CC syncytial virus (HRSV) nucleoprotein; this interaction inhibits EIF2AK2
CC phosphorylation of EIF2S1 and blocks EIF2AK2-mediated translation
CC shutoff. {ECO:0000269|PubMed:20519500}.
CC -!- INTERACTION:
CC P19525; P78563-4: ADARB1; NbExp=3; IntAct=EBI-640775, EBI-12002366;
CC P19525; P06493: CDK1; NbExp=4; IntAct=EBI-640775, EBI-444308;
CC P19525; Q7L2E3: DHX30; NbExp=4; IntAct=EBI-640775, EBI-1211456;
CC P19525; Q96C10: DHX58; NbExp=2; IntAct=EBI-640775, EBI-744193;
CC P19525; Q08211: DHX9; NbExp=2; IntAct=EBI-640775, EBI-352022;
CC P19525; Q9UPY3: DICER1; NbExp=2; IntAct=EBI-640775, EBI-395506;
CC P19525; Q6P2E9: EDC4; NbExp=2; IntAct=EBI-640775, EBI-1006038;
CC P19525; P19525: EIF2AK2; NbExp=2; IntAct=EBI-640775, EBI-640775;
CC P19525; P05198: EIF2S1; NbExp=5; IntAct=EBI-640775, EBI-1056162;
CC P19525; P56537: EIF6; NbExp=2; IntAct=EBI-640775, EBI-372243;
CC P19525; Q8IY81: FTSJ3; NbExp=3; IntAct=EBI-640775, EBI-744088;
CC P19525; Q9HCE1: MOV10; NbExp=3; IntAct=EBI-640775, EBI-1055820;
CC P19525; Q96P20: NLRP3; NbExp=6; IntAct=EBI-640775, EBI-6253230;
CC P19525; P06748: NPM1; NbExp=3; IntAct=EBI-640775, EBI-78579;
CC P19525; O75569: PRKRA; NbExp=6; IntAct=EBI-640775, EBI-713955;
CC P19525; O75569-1: PRKRA; NbExp=3; IntAct=EBI-640775, EBI-15588172;
CC P19525; Q9NUL3: STAU2; NbExp=3; IntAct=EBI-640775, EBI-722938;
CC P19525; Q15633: TARBP2; NbExp=2; IntAct=EBI-640775, EBI-978581;
CC P19525; Q9H0E2: TOLLIP; NbExp=2; IntAct=EBI-640775, EBI-74615;
CC P19525; Q9UL40: ZNF346; NbExp=3; IntAct=EBI-640775, EBI-2462313;
CC P19525; Q27968: DNAJC3; Xeno; NbExp=5; IntAct=EBI-640775, EBI-640793;
CC P19525; P20639: K3L; Xeno; NbExp=3; IntAct=EBI-640775, EBI-8674942;
CC P19525; P0DTC9: N; Xeno; NbExp=8; IntAct=EBI-640775, EBI-25475856;
CC P19525; P04487: US11; Xeno; NbExp=3; IntAct=EBI-640775, EBI-6150681;
CC P19525; Q2HR71: vIRF-2; Xeno; NbExp=2; IntAct=EBI-640775, EBI-8876177;
CC P19525; PRO_0000278746 [O92972]; Xeno; NbExp=2; IntAct=EBI-640775, EBI-6918883;
CC P19525; PRO_0000037570 [P27958]; Xeno; NbExp=4; IntAct=EBI-640775, EBI-6904269;
CC P19525; PRO_0000037576 [P27958]; Xeno; NbExp=5; IntAct=EBI-640775, EBI-8753518;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15121867,
CC ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:22214662}. Nucleus
CC {ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:21072047}. Cytoplasm,
CC perinuclear region {ECO:0000269|PubMed:15121867}. Note=Nuclear
CC localization is elevated in acute leukemia, myelodysplastic syndrome
CC (MDS), melanoma, breast, colon, prostate and lung cancer patient
CC samples or cell lines as well as neurocytes from advanced Creutzfeldt-
CC Jakob disease patients. {ECO:0000269|PubMed:21072047}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P19525-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P19525-2; Sequence=VSP_046177;
CC -!- TISSUE SPECIFICITY: Highly expressed in thymus, spleen and bone marrow
CC compared to non-hematopoietic tissues such as small intestine, liver,
CC or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer
CC disease (AD) brain. Elevated levels seen in breast and colon
CC carcinomas, and which correlates with tumor progression and
CC invasiveness or risk of progression. {ECO:0000269|PubMed:21029237,
CC ECO:0000269|PubMed:23403623}.
CC -!- INDUCTION: By type I interferons. {ECO:0000269|PubMed:1695551}.
CC -!- PTM: Autophosphorylated on several Ser, Thr and Tyr residues.
CC Autophosphorylation of Thr-451 is dependent on Thr-446 and is
CC stimulated by dsRNA binding and dimerization. Autophosphorylation
CC apparently leads to the activation of the kinase. Tyrosine
CC autophosphorylation is essential for efficient dsRNA-binding,
CC dimerization, and kinase activation. {ECO:0000269|PubMed:11152499,
CC ECO:0000269|PubMed:11337501, ECO:0000269|PubMed:16179258,
CC ECO:0000269|PubMed:16373505, ECO:0000269|PubMed:20685959,
CC ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:21072047}.
CC -!- DISEASE: Leukoencephalopathy, developmental delay, and episodic
CC neurologic regression syndrome (LEUDEN) [MIM:618877]: An autosomal
CC dominant disorder characterized by global developmental delay apparent
CC in early childhood, cognitive impairment, ataxia, poor or absent speech
CC with dysarthria, hypotonia, hypertonia, extrapyramidal signs, tremor,
CC and abnormal involuntary movements. Affected individuals also exhibit
CC neurological regression in the setting of febrile illness or infection.
CC Many patients have seizures. Brain imaging shows diffuse white matter
CC abnormalities with poor myelination. {ECO:0000269|PubMed:32197074}.
CC Note=The disease may be caused by variants affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/prkr/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/EIF2AK2ID41866ch2p22.html";
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DR EMBL; M35663; AAA36409.1; -; mRNA.
DR EMBL; M85294; AAA18253.1; -; mRNA.
DR EMBL; U50648; AAC50768.1; -; Genomic_DNA.
DR EMBL; U50634; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50635; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50636; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50637; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50638; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50639; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50640; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50641; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50642; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50643; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50644; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50645; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50646; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; U50647; AAC50768.1; JOINED; Genomic_DNA.
DR EMBL; AF167472; AAF13156.1; -; Genomic_DNA.
DR EMBL; AF167460; AAF13156.1; JOINED; Genomic_DNA.
DR EMBL; AF167462; AAF13156.1; JOINED; Genomic_DNA.
DR EMBL; AF167463; AAF13156.1; JOINED; Genomic_DNA.
DR EMBL; AF167464; AAF13156.1; JOINED; Genomic_DNA.
DR EMBL; AF167465; AAF13156.1; JOINED; Genomic_DNA.
DR EMBL; AF167466; AAF13156.1; JOINED; Genomic_DNA.
DR EMBL; AF167468; AAF13156.1; JOINED; Genomic_DNA.
DR EMBL; AF167470; AAF13156.1; JOINED; Genomic_DNA.
DR EMBL; AY302136; AAP57628.1; -; mRNA.
DR EMBL; AK290655; BAF83344.1; -; mRNA.
DR EMBL; AK313818; BAG36554.1; -; mRNA.
DR EMBL; AY228338; AAO38055.1; -; Genomic_DNA.
DR EMBL; AC007899; AAY24317.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00407.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00408.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00409.1; -; Genomic_DNA.
DR EMBL; BC093676; AAH93676.1; -; mRNA.
DR EMBL; BC101475; AAI01476.1; -; mRNA.
DR CCDS; CCDS1786.1; -. [P19525-1]
DR CCDS; CCDS46259.1; -. [P19525-2]
DR PIR; JC5225; JC5225.
DR RefSeq; NP_001129123.1; NM_001135651.2. [P19525-1]
DR RefSeq; NP_001129124.1; NM_001135652.2. [P19525-2]
DR RefSeq; NP_002750.1; NM_002759.3. [P19525-1]
DR RefSeq; XP_011531289.1; XM_011532987.2. [P19525-1]
DR PDB; 1QU6; NMR; -; A=1-170.
DR PDB; 2A19; X-ray; 2.50 A; B/C=258-550.
DR PDB; 2A1A; X-ray; 2.80 A; B=258-550.
DR PDB; 3UIU; X-ray; 2.90 A; A/B=254-551.
DR PDB; 6D3K; X-ray; 2.60 A; A/B/C=229-551.
DR PDB; 6D3L; X-ray; 3.10 A; A=229-551.
DR PDBsum; 1QU6; -.
DR PDBsum; 2A19; -.
DR PDBsum; 2A1A; -.
DR PDBsum; 3UIU; -.
DR PDBsum; 6D3K; -.
DR PDBsum; 6D3L; -.
DR AlphaFoldDB; P19525; -.
DR BMRB; P19525; -.
DR SMR; P19525; -.
DR BioGRID; 111596; 290.
DR DIP; DIP-2657N; -.
DR IntAct; P19525; 133.
DR MINT; P19525; -.
DR STRING; 9606.ENSP00000233057; -.
DR BindingDB; P19525; -.
DR ChEMBL; CHEMBL5785; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB00328; Indomethacin.
DR DrugCentral; P19525; -.
DR GuidetoPHARMACOLOGY; 2016; -.
DR GlyGen; P19525; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P19525; -.
DR PhosphoSitePlus; P19525; -.
DR SwissPalm; P19525; -.
DR BioMuta; EIF2AK2; -.
DR DMDM; 125527; -.
DR EPD; P19525; -.
DR jPOST; P19525; -.
DR MassIVE; P19525; -.
DR MaxQB; P19525; -.
DR PaxDb; P19525; -.
DR PeptideAtlas; P19525; -.
DR PRIDE; P19525; -.
DR ProteomicsDB; 19391; -.
DR ProteomicsDB; 53670; -. [P19525-1]
DR TopDownProteomics; P19525-1; -. [P19525-1]
DR Antibodypedia; 3548; 1198 antibodies from 43 providers.
DR DNASU; 5610; -.
DR Ensembl; ENST00000233057.9; ENSP00000233057.4; ENSG00000055332.19. [P19525-1]
DR Ensembl; ENST00000395127.6; ENSP00000378559.2; ENSG00000055332.19. [P19525-1]
DR Ensembl; ENST00000405334.5; ENSP00000385014.1; ENSG00000055332.19. [P19525-2]
DR Ensembl; ENST00000647926.1; ENSP00000497534.1; ENSG00000055332.19. [P19525-1]
DR Ensembl; ENST00000679507.1; ENSP00000506024.1; ENSG00000055332.19. [P19525-1]
DR Ensembl; ENST00000681463.1; ENSP00000505138.1; ENSG00000055332.19. [P19525-1]
DR Ensembl; ENST00000681507.1; ENSP00000505772.1; ENSG00000055332.19. [P19525-1]
DR GeneID; 5610; -.
DR KEGG; hsa:5610; -.
DR MANE-Select; ENST00000233057.9; ENSP00000233057.4; NM_001135651.3; NP_001129123.1.
DR UCSC; uc010fab.3; human. [P19525-1]
DR CTD; 5610; -.
DR DisGeNET; 5610; -.
DR GeneCards; EIF2AK2; -.
DR HGNC; HGNC:9437; EIF2AK2.
DR HPA; ENSG00000055332; Low tissue specificity.
DR MalaCards; EIF2AK2; -.
DR MIM; 176871; gene.
DR MIM; 618877; phenotype.
DR neXtProt; NX_P19525; -.
DR OpenTargets; ENSG00000055332; -.
DR Orphanet; 256; Early-onset generalized limb-onset dystonia.
DR PharmGKB; PA33779; -.
DR VEuPathDB; HostDB:ENSG00000055332; -.
DR eggNOG; KOG1033; Eukaryota.
DR GeneTree; ENSGT00940000160736; -.
DR HOGENOM; CLU_023682_1_0_1; -.
DR InParanoid; P19525; -.
DR OMA; LIQMEFC; -.
DR PhylomeDB; P19525; -.
DR TreeFam; TF317576; -.
DR PathwayCommons; P19525; -.
DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
DR Reactome; R-HSA-169131; Inhibition of PKR.
DR SignaLink; P19525; -.
DR SIGNOR; P19525; -.
DR BioGRID-ORCS; 5610; 12 hits in 1110 CRISPR screens.
DR ChiTaRS; EIF2AK2; human.
DR EvolutionaryTrace; P19525; -.
DR GeneWiki; Protein_kinase_R; -.
DR GenomeRNAi; 5610; -.
DR Pharos; P19525; Tchem.
DR PRO; PR:P19525; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P19525; protein.
DR Bgee; ENSG00000055332; Expressed in endometrium epithelium and 209 other tissues.
DR Genevisible; P19525; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005840; C:ribosome; TAS:AgBase.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003725; F:double-stranded RNA binding; IDA:MGI.
DR GO; GO:0004694; F:eukaryotic translation initiation factor 2alpha kinase activity; IMP:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0019888; F:protein phosphatase regulator activity; TAS:ProtInc.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:ProtInc.
DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR GO; GO:0034198; P:cellular response to amino acid starvation; IMP:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IEP:ARUK-UCL.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc.
DR GO; GO:0033689; P:negative regulation of osteoblast proliferation; IMP:UniProtKB.
DR GO; GO:0017148; P:negative regulation of translation; IDA:UniProtKB.
DR GO; GO:0045071; P:negative regulation of viral genome replication; IMP:UniProtKB.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISS:UniProtKB.
DR GO; GO:0001819; P:positive regulation of cytokine production; ISS:UniProtKB.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:1901532; P:regulation of hematopoietic progenitor cell differentiation; ISS:UniProtKB.
DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; ISS:UniProtKB.
DR GO; GO:1902033; P:regulation of hematopoietic stem cell proliferation; ISS:UniProtKB.
DR GO; GO:1900225; P:regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
DR GO; GO:0035455; P:response to interferon-alpha; IDA:UniProtKB.
DR GO; GO:0009615; P:response to virus; IMP:UniProtKB.
DR GO; GO:0006412; P:translation; IEA:Ensembl.
DR CDD; cd19903; DSRM_EIF2AK2_rpt1; 1.
DR CDD; cd19904; DSRM_EIF2AK2_rpt2; 1.
DR IDEAL; IID00443; -.
DR InterPro; IPR014720; dsRBD_dom.
DR InterPro; IPR044452; EIF2AK2_DSRM_1.
DR InterPro; IPR044453; EIF2AK2_DSRM_2.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00035; dsrm; 2.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00358; DSRM; 2.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50137; DS_RBD; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Antiviral defense;
KW ATP-binding; Cytoplasm; Direct protein sequencing; Host-virus interaction;
KW Immunity; Innate immunity; Isopeptide bond; Kinase; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Repeat; RNA-binding;
KW Serine/threonine-protein kinase; Transcription; Transcription regulation;
KW Transferase; Tyrosine-protein kinase; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PubMed:22223895,
FT ECO:0007744|PubMed:22814378"
FT CHAIN 2..551
FT /note="Interferon-induced, double-stranded RNA-activated
FT protein kinase"
FT /id="PRO_0000085945"
FT DOMAIN 9..77
FT /note="DRBM 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266"
FT DOMAIN 100..167
FT /note="DRBM 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266"
FT DOMAIN 267..538
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REPEAT 331..343
FT /note="1"
FT REPEAT 345..357
FT /note="2"
FT REGION 2..180
FT /note="(Microbial infection) Interaction with HCV NS5A"
FT /evidence="ECO:0000269|PubMed:17267064"
FT REGION 202..222
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 266..551
FT /note="Interaction with TRAF5"
FT /evidence="ECO:0000269|PubMed:15121867"
FT REGION 331..357
FT /note="2 X 13 AA approximate repeats"
FT ACT_SITE 414
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 273..281
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 296
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000269|Ref.13, ECO:0007744|PubMed:22223895,
FT ECO:0007744|PubMed:22814378"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:11152499,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231"
FT MOD_RES 88
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000305|PubMed:11152499"
FT MOD_RES 89
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000305|PubMed:11152499"
FT MOD_RES 90
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000305|PubMed:11152499"
FT MOD_RES 101
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:16373505"
FT MOD_RES 162
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:16373505"
FT MOD_RES 242
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000305|PubMed:11152499"
FT MOD_RES 255
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000305|PubMed:11152499"
FT MOD_RES 258
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000305|PubMed:11152499"
FT MOD_RES 293
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:16373505"
FT MOD_RES 446
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11337501,
FT ECO:0000269|PubMed:16179258"
FT MOD_RES 451
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11337501,
FT ECO:0000269|PubMed:20685959"
FT MOD_RES 456
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 542
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 69
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000269|PubMed:23229543"
FT CROSSLNK 159
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000269|PubMed:23229543"
FT VAR_SEQ 263..303
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.7"
FT /id="VSP_046177"
FT VARIANT 11
FT /note="M -> L (in LEUDEN; unknown pathological
FT significance; reduced phosphorylation of eukaryotic
FT translation initiation factor 2-alpha in patient cells)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084260"
FT VARIANT 32
FT /note="N -> S (in LEUDEN; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084261"
FT VARIANT 97
FT /note="S -> F (in LEUDEN; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084262"
FT VARIANT 109
FT /note="A -> S (in LEUDEN; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084263"
FT VARIANT 109
FT /note="A -> V (in LEUDEN; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084264"
FT VARIANT 114
FT /note="L -> Q (found in a patient with dysmorphic facies,
FT syndactyly, congenital microcephaly and global
FT developmental delay; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084265"
FT VARIANT 133
FT /note="Y -> F (in LEUDEN; unknown pathological
FT significance; reduced phosphorylation of eukaryotic
FT translation initiation factor 2-alpha in patient cells)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084266"
FT VARIANT 325
FT /note="G -> S (in LEUDEN; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084267"
FT VARIANT 428
FT /note="V -> E (in dbSNP:rs56219559)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040474"
FT VARIANT 439
FT /note="L -> V (in a lung adenocarcinoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040475"
FT VARIANT 461
FT /note="S -> C (in LEUDEN; unknown pathological
FT significance; reduced phosphorylation of eukaryotic
FT translation initiation factor 2-alpha in patient cells)"
FT /evidence="ECO:0000269|PubMed:32197074"
FT /id="VAR_084268"
FT VARIANT 506
FT /note="I -> V (in dbSNP:rs34821155)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040476"
FT MUTAGEN 59..60
FT /note="SK->AA: In FL-PKR-2AI; moderate loss of activity but
FT no effect on dsRNA binding."
FT /evidence="ECO:0000269|PubMed:11337501"
FT MUTAGEN 60
FT /note="K->A: Impairs dsRNA binding but not dimerization or
FT activity."
FT /evidence="ECO:0000269|PubMed:11337501"
FT MUTAGEN 67
FT /note="A->E: Significant loss of activity; loss of dsRNA
FT binding and dimerization."
FT /evidence="ECO:0000269|PubMed:11337501"
FT MUTAGEN 83
FT /note="S->A: No effect on enzymatic activity; when
FT associated with A-88; A-89 and A-90."
FT /evidence="ECO:0000269|PubMed:11152499"
FT MUTAGEN 88
FT /note="T->A: No effect on enzymatic activity; when
FT associated with A-83; A-89 and A-90."
FT /evidence="ECO:0000269|PubMed:11152499"
FT MUTAGEN 89
FT /note="T->A: No effect on enzymatic activity; when
FT associated with A-83; A-88 and A-90."
FT /evidence="ECO:0000269|PubMed:11152499"
FT MUTAGEN 90
FT /note="T->A: No effect on enzymatic activity; when
FT associated with A-83; A-88 and A-89."
FT /evidence="ECO:0000269|PubMed:11152499"
FT MUTAGEN 149..150
FT /note="TK->AA: In FL-PKR-2AII; no effect on activity."
FT /evidence="ECO:0000269|PubMed:11337501"
FT MUTAGEN 242
FT /note="S->A: Moderate loss of activity; when associated
FT with A-255 and A-258."
FT /evidence="ECO:0000269|PubMed:11152499"
FT MUTAGEN 244..296
FT /note="Missing: Loss of activity."
FT /evidence="ECO:0000269|PubMed:11337501"
FT MUTAGEN 255
FT /note="T->A: Moderate loss of activity; when associated
FT with A-242 and A-255."
FT /evidence="ECO:0000269|PubMed:11152499"
FT MUTAGEN 258
FT /note="T->A: Moderate loss of activity."
FT /evidence="ECO:0000269|PubMed:11152499"
FT MUTAGEN 296
FT /note="K->R: Loss of activity."
FT /evidence="ECO:0000269|PubMed:11152499"
FT MUTAGEN 446
FT /note="T->A: Significant loss of activity and impairs
FT autophosphorylation of T-451."
FT /evidence="ECO:0000269|PubMed:11337501"
FT MUTAGEN 451
FT /note="T->A: Loss of activity."
FT /evidence="ECO:0000269|PubMed:11337501"
FT CONFLICT 102
FT /note="I -> M (in Ref. 7; AAP57628)"
FT /evidence="ECO:0000305"
FT CONFLICT 224
FT /note="S -> R (in Ref. 7; AAP57628)"
FT /evidence="ECO:0000305"
FT CONFLICT 512
FT /note="K -> E (in Ref. 6; AAF13156)"
FT /evidence="ECO:0000305"
FT STRAND 5..7
FT /evidence="ECO:0007829|PDB:1QU6"
FT HELIX 10..21
FT /evidence="ECO:0007829|PDB:1QU6"
FT STRAND 26..32
FT /evidence="ECO:0007829|PDB:1QU6"
FT TURN 35..37
FT /evidence="ECO:0007829|PDB:1QU6"
FT STRAND 41..50
FT /evidence="ECO:0007829|PDB:1QU6"
FT STRAND 54..56
FT /evidence="ECO:0007829|PDB:1QU6"
FT HELIX 61..76
FT /evidence="ECO:0007829|PDB:1QU6"
FT HELIX 102..111
FT /evidence="ECO:0007829|PDB:1QU6"
FT STRAND 115..123
FT /evidence="ECO:0007829|PDB:1QU6"
FT STRAND 125..138
FT /evidence="ECO:0007829|PDB:1QU6"
FT STRAND 144..149
FT /evidence="ECO:0007829|PDB:1QU6"
FT HELIX 150..167
FT /evidence="ECO:0007829|PDB:1QU6"
FT HELIX 261..266
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 267..274
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 276..278
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 281..286
FT /evidence="ECO:0007829|PDB:2A19"
FT TURN 287..289
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 292..299
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 303..305
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 306..314
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 323..332
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 358..366
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 374..380
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 381..383
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 388..407
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 410..412
FT /evidence="ECO:0007829|PDB:2A1A"
FT HELIX 417..419
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 420..424
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 427..430
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 433..435
FT /evidence="ECO:0007829|PDB:6D3L"
FT STRAND 437..440
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 457..461
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 468..482
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 488..499
FT /evidence="ECO:0007829|PDB:2A19"
FT STRAND 505..507
FT /evidence="ECO:0007829|PDB:3UIU"
FT HELIX 509..518
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 523..525
FT /evidence="ECO:0007829|PDB:2A19"
FT HELIX 529..539
FT /evidence="ECO:0007829|PDB:2A19"
SQ SEQUENCE 551 AA; 62094 MW; 815AD83ACAB45DA3 CRC64;
MAGDLSAGFF MEELNTYRQK QGVVLKYQEL PNSGPPHDRR FTFQVIIDGR EFPEGEGRSK
KEAKNAAAKL AVEILNKEKK AVSPLLLTTT NSSEGLSMGN YIGLINRIAQ KKRLTVNYEQ
CASGVHGPEG FHYKCKMGQK EYSIGTGSTK QEAKQLAAKL AYLQILSEET SVKSDYLSSG
SFATTCESQS NSLVTSTLAS ESSSEGDFSA DTSEINSNSD SLNSSSLLMN GLRNNQRKAK
RSLAPRFDLP DMKETKYTVD KRFGMDFKEI ELIGSGGFGQ VFKAKHRIDG KTYVIKRVKY
NNEKAEREVK ALAKLDHVNI VHYNGCWDGF DYDPETSDDS LESSDYDPEN SKNSSRSKTK
CLFIQMEFCD KGTLEQWIEK RRGEKLDKVL ALELFEQITK GVDYIHSKKL IHRDLKPSNI
FLVDTKQVKI GDFGLVTSLK NDGKRTRSKG TLRYMSPEQI SSQDYGKEVD LYALGLILAE
LLHVCDTAFE TSKFFTDLRD GIISDIFDKK EKTLLQKLLS KKPEDRPNTS EILRTLTVWK
KSPEKNERHT C
