E2AK2_MOUSE
ID E2AK2_MOUSE Reviewed; 515 AA.
AC Q03963; Q61742; Q62026;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 2.
DT 03-AUG-2022, entry version 194.
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:20478537};
DE AltName: Full=Serine/threonine-protein kinase TIK;
DE AltName: Full=Tyrosine-protein kinase EIF2AK2;
DE EC=2.7.10.2;
DE AltName: Full=p68 kinase;
GN Name=Eif2ak2; Synonyms=Pkr, Prkr, Tik;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1714905; DOI=10.1016/s0021-9258(18)98517-0;
RA Icely P.L., Gros P., Bergeron J.J.M., Devault A., Afar D.E.H., Bell J.C.;
RT "TIK, a novel serine/threonine kinase, is recognized by antibodies directed
RT against phosphotyrosine.";
RL J. Biol. Chem. 266:16073-16077(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Mammary carcinoma;
RX PubMed=1351683; DOI=10.1073/pnas.89.12.5447;
RA Feng G.S., Chong K., Kumar A., Williams B.R.G.;
RT "Identification of double-stranded RNA-binding domains in the interferon-
RT induced double-stranded RNA-activated p68 kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:5447-5451(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=DBA/2J; TISSUE=Liver;
RX PubMed=7914700; DOI=10.1073/pnas.91.17.7995;
RA Tanaka H., Samuel C.E.;
RT "Mechanism of interferon action: structure of the mouse PKR gene encoding
RT the interferon-inducible RNA-dependent protein kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:7995-7999(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=DBA/2J; TISSUE=Liver;
RX PubMed=7533117; DOI=10.1016/0378-1119(94)00821-9;
RA Tanaka H., Samuel C.E.;
RT "Sequence of the murine interferon-inducible RNA-dependent protein kinase
RT (PKR) deduced from genomic clones.";
RL Gene 153:283-284(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Skin;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [6]
RP 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 [7]
RP INTERACTION WITH NPM1.
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 [8]
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 [9]
RP FUNCTION IN SFV RESTRICTION.
RX PubMed=19264662; DOI=10.1099/vir.0.007336-0;
RA Barry G., Breakwell L., Fragkoudis R., Attarzadeh-Yazdi G.,
RA Rodriguez-Andres J., Kohl A., Fazakerley J.K.;
RT "PKR acts early in infection to suppress Semliki Forest virus production
RT and strongly enhances the type I interferon response.";
RL J. Gen. Virol. 90:1382-1391(2009).
RN [10]
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 [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [12]
RP FUNCTION.
RX PubMed=20478537; DOI=10.1016/j.chom.2010.04.007;
RA Schulz O., Pichlmair A., Rehwinkel J., Rogers N.C., Scheuner D., Kato H.,
RA Takeuchi O., Akira S., Kaufman R.J., Reis e Sousa C.;
RT "Protein kinase R contributes to immunity against specific viruses by
RT regulating interferon mRNA integrity.";
RL Cell Host Microbe 7:354-361(2010).
RN [13]
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 [14]
RP FUNCTION.
RX PubMed=20038207; DOI=10.1089/jir.2009.0051;
RA Minor R.A., Limmon G.V., Miller-DeGraff L., Dixon D., Andrews D.M.,
RA Kaufman R.J., Imani F.;
RT "Double-stranded RNA-activated protein kinase regulates early innate immune
RT responses during respiratory syncytial virus infection.";
RL J. Interferon Cytokine Res. 30:263-272(2010).
RN [15]
RP FUNCTION.
RX PubMed=20631127; DOI=10.1128/jvi.00625-10;
RA Rojas M., Arias C.F., Lopez S.;
RT "Protein kinase R is responsible for the phosphorylation of eIF2alpha in
RT rotavirus infection.";
RL J. Virol. 84:10457-10466(2010).
RN [16]
RP FUNCTION IN LCMV RESTRICTION.
RX PubMed=20585572; DOI=10.1371/journal.ppat.1000966;
RA Nakayama Y., Plisch E.H., Sullivan J., Thomas C., Czuprynski C.J.,
RA Williams B.R., Suresh M.;
RT "Role of PKR and Type I IFNs in viral control during primary and secondary
RT infection.";
RL PLoS Pathog. 6:E1000966-E1000966(2010).
RN [17]
RP FUNCTION.
RX PubMed=21994357; DOI=10.1128/cvi.05476-11;
RA Thakur S.A., Zalinger Z.B., Johnson T.R., Imani F.;
RT "Protein kinase R is a novel mediator of CD40 signaling and plays a
RT critical role in modulating immunoglobulin expression during respiratory
RT syncytial virus infection.";
RL Clin. Vaccine Immunol. 18:2060-2066(2011).
RN [18]
RP REVIEW.
RX PubMed=21300116; DOI=10.1016/j.jhep.2010.11.037;
RA Marsollier N., Ferre P., Foufelle F.;
RT "Novel insights in the interplay between inflammation and metabolic
RT diseases: a role for the pathogen sensing kinase PKR.";
RL J. Hepatol. 54:1307-1309(2011).
RN [19]
RP FUNCTION, AND INTERACTION WITH IRS1.
RX PubMed=22948222; DOI=10.1210/en.2012-1400;
RA Carvalho-Filho M.A., Carvalho B.M., Oliveira A.G., Guadagnini D., Ueno M.,
RA Dias M.M., Tsukumo D.M., Hirabara S.M., Reis L.F., Curi R.,
RA Carvalheira J.B., Saad M.J.;
RT "Double-stranded RNA-activated protein kinase is a key modulator of insulin
RT sensitivity in physiological conditions and in obesity in mice.";
RL Endocrinology 153:5261-5274(2012).
RN [20]
RP FUNCTION, AND INTERACTION WITH GSN.
RX PubMed=22633459; DOI=10.1016/j.immuni.2012.02.020;
RA Irving A.T., Wang D., Vasilevski O., Latchoumanin O., Kozer N.,
RA Clayton A.H., Szczepny A., Morimoto H., Xu D., Williams B.R., Sadler A.J.;
RT "Regulation of actin dynamics by protein kinase R control of gelsolin
RT enforces basal innate immune defense.";
RL Immunity 36:795-806(2012).
RN [21]
RP FUNCTION, INTERACTION WITH NLRP3, AND 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 [22]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
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 [23]
RP FUNCTION.
RX PubMed=23401008; DOI=10.1002/eji.201243187;
RA He Y., Franchi L., Nunez G.;
RT "The protein kinase PKR is critical for LPS-induced iNOS production but
RT dispensable for inflammasome activation in macrophages.";
RL Eur. J. Immunol. 43:1147-1152(2013).
RN [24]
RP ISGYLATION.
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 [25]
RP FUNCTION.
RX PubMed=23392680; DOI=10.1523/jneurosci.2322-12.2013;
RA Stern E., Chinnakkaruppan A., David O., Sonenberg N., Rosenblum K.;
RT "Blocking the eIF2? kinase (PKR) enhances positive and negative forms of
RT cortex-dependent taste memory.";
RL J. Neurosci. 33:2517-2525(2013).
RN [26]
RP STRUCTURE BY NMR OF 1-171.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the first and second DSRM domain in interferon-
RT induced, double-stranded RNA-activated protein kinase.";
RL Submitted (NOV-2005) to the PDB data bank.
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:20038207,
CC PubMed:20478537, PubMed:21123651). Inhibits viral replication via the
CC integrated stress response (ISR): EIF2S1/eIF-2-alpha phosphorylation in
CC response to viral infection converts EIF2S1/eIF-2-alpha in a global
CC protein synthesis inhibitor, resulting to a shutdown of cellular and
CC viral protein synthesis, while concomitantly initiating the
CC preferential translation of ISR-specific mRNAs, such as the
CC transcriptional activator ATF4 (PubMed:21123651, PubMed:20631127).
CC Exerts its antiviral activity on a wide range of DNA and RNA viruses
CC including west nile virus (WNV), sindbis virus (SV), foot-and-mouth
CC virus (FMDV), semliki Forest virus (SFV) and lymphocytic
CC choriomeningitis virus (LCMV) (PubMed:19264662, PubMed:20585572,
CC PubMed:20631127, PubMed:21994357). Also involved in the regulation of
CC signal transduction, apoptosis, cell proliferation and differentiation:
CC phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9,
CC ILF3, and IRS1 (PubMed:19229320, PubMed:23403623). In addition to
CC serine/threonine-protein kinase activity, also has tyrosine-protein
CC kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage,
CC facilitating its ubiquitination and proteosomal degradation (By
CC similarity). Either as an adapter protein and/or via its kinase
CC activity, can regulate various signaling pathways (p38 MAP kinase, NF-
CC kappa-B and insulin signaling pathways) and transcription factors (JUN,
CC STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding
CC pro-inflammatory cytokines and IFNs (PubMed:22948222, PubMed:23392680).
CC Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF
CC family of proteins and activates the p38 MAP kinase pathway via
CC interaction with MAP2K6 (By similarity). Can act as both a positive and
CC negative regulator of the insulin signaling pathway (ISP) (By
CC similarity). Negatively regulates ISP by inducing the inhibitory
CC phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and
CC positively regulates ISP via phosphorylation of PPP2R5A which activates
CC FOXO1, which in turn up-regulates the expression of insulin receptor
CC substrate 2 (IRS2) (By similarity). Can regulate NLRP3 inflammasome
CC assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4
CC inflammasomes (PubMed:22801494, PubMed:23401008). 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 (PubMed:22633459). {ECO:0000250|UniProtKB:P19525,
CC ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19264662,
CC ECO:0000269|PubMed:20038207, ECO:0000269|PubMed:20478537,
CC ECO:0000269|PubMed:20585572, ECO:0000269|PubMed:20631127,
CC ECO:0000269|PubMed:21123651, ECO:0000269|PubMed:21994357,
CC ECO:0000269|PubMed:22633459, ECO:0000269|PubMed:22801494,
CC ECO:0000269|PubMed:22948222, ECO:0000269|PubMed:23392680,
CC ECO:0000269|PubMed:23401008, ECO:0000269|PubMed:23403623}.
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 cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR (By similarity).
CC {ECO:0000250|UniProtKB:P19525}.
CC -!- SUBUNIT: Homodimer. Interacts with DNAJC3 and STRBP (By similarity).
CC Forms a complex with FANCA, FANCC, FANCG and HSP70 (By similarity).
CC Interacts with ADAR/ADAR1. The inactive form interacts with NCK1.
CC Interacts (via the kinase catalytic domain) with STAT3 (via SH2
CC domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus).
CC Interacts with MAP2K6, TARBP2, NLRP1, NLRC4 and AIM2. Interacts (via
CC DRBM 1 domain) with DUS2L (via DRBM domain) (By similarity). Interacts
CC with DHX9 (via N-terminus) and this interaction is dependent upon
CC activation of the kinase. The inactive form interacts with GSN.
CC Interacts with IKBKB/IKKB, NPM1, NLRP3 and IRS1.
CC {ECO:0000250|UniProtKB:P19525, ECO:0000269|PubMed:10848580,
CC ECO:0000269|PubMed:12882984, ECO:0000269|PubMed:17079286,
CC ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:22633459,
CC ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:22948222}.
CC -!- INTERACTION:
CC Q03963; P35569: Irs1; NbExp=2; IntAct=EBI-2603444, EBI-400825;
CC Q03963; Q8R4B8: Nlrp3; NbExp=3; IntAct=EBI-2603444, EBI-6910832;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P19525}. Nucleus
CC {ECO:0000250|UniProtKB:P19525}. Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:P19525}.
CC -!- TISSUE SPECIFICITY: Expressed in heart, lung, brain, kidney, testes,
CC thymus and bone marrow.
CC -!- INDUCTION: By type I interferons. {ECO:0000250}.
CC -!- PTM: Autophosphorylated on several Ser, Thr and Tyr residues.
CC Autophosphorylation of Thr-414 is dependent on Thr-409 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 (By similarity).
CC {ECO:0000250|UniProtKB:P19525}.
CC -!- DISRUPTION PHENOTYPE: Mice have significantly elevated numbers of bone
CC marrow derived hematopoietic stem/progenitor cells (HSPCs) and which
CC are more actively proliferating and resistant to stress.
CC {ECO:0000269|PubMed:23403623}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. GCN2 subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; M65029; AAA40150.1; -; mRNA.
DR EMBL; M93567; AAA39885.1; -; mRNA.
DR EMBL; U09928; AAC24729.1; -; Genomic_DNA.
DR EMBL; U09914; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09915; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09916; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09917; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09918; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09919; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09920; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09921; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09922; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09923; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09924; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09925; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09926; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; U09927; AAC24729.1; JOINED; Genomic_DNA.
DR EMBL; AK028602; BAC26027.1; -; mRNA.
DR CCDS; CCDS28980.1; -.
DR PIR; A59309; A59309.
DR RefSeq; NP_035293.1; NM_011163.4.
DR PDB; 1X48; NMR; -; A=96-170.
DR PDB; 1X49; NMR; -; A=1-84.
DR PDBsum; 1X48; -.
DR PDBsum; 1X49; -.
DR AlphaFoldDB; Q03963; -.
DR SMR; Q03963; -.
DR BioGRID; 202376; 11.
DR DIP; DIP-41411N; -.
DR IntAct; Q03963; 4.
DR STRING; 10090.ENSMUSP00000024884; -.
DR ChEMBL; CHEMBL1795121; -.
DR iPTMnet; Q03963; -.
DR PhosphoSitePlus; Q03963; -.
DR SwissPalm; Q03963; -.
DR EPD; Q03963; -.
DR jPOST; Q03963; -.
DR MaxQB; Q03963; -.
DR PaxDb; Q03963; -.
DR PeptideAtlas; Q03963; -.
DR PRIDE; Q03963; -.
DR ProteomicsDB; 275423; -.
DR Antibodypedia; 3548; 1198 antibodies from 43 providers.
DR DNASU; 19106; -.
DR Ensembl; ENSMUST00000024884; ENSMUSP00000024884; ENSMUSG00000024079.
DR GeneID; 19106; -.
DR KEGG; mmu:19106; -.
DR UCSC; uc008dph.2; mouse.
DR CTD; 5610; -.
DR MGI; MGI:1353449; Eif2ak2.
DR VEuPathDB; HostDB:ENSMUSG00000024079; -.
DR eggNOG; KOG1033; Eukaryota.
DR GeneTree; ENSGT00940000160736; -.
DR HOGENOM; CLU_023682_1_0_1; -.
DR InParanoid; Q03963; -.
DR OMA; LIQMEFC; -.
DR OrthoDB; 1195366at2759; -.
DR PhylomeDB; Q03963; -.
DR TreeFam; TF317576; -.
DR Reactome; R-MMU-1169408; ISG15 antiviral mechanism.
DR BioGRID-ORCS; 19106; 6 hits in 78 CRISPR screens.
DR ChiTaRS; Eif2ak2; mouse.
DR EvolutionaryTrace; Q03963; -.
DR PRO; PR:Q03963; -.
DR Proteomes; UP000000589; Chromosome 17.
DR RNAct; Q03963; protein.
DR Bgee; ENSMUSG00000024079; Expressed in small intestine Peyer's patch and 241 other tissues.
DR Genevisible; Q03963; MM.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
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; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004672; F:protein kinase activity; IDA:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0034198; P:cellular response to amino acid starvation; ISO:MGI.
DR GO; GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IDA:MGI.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IGI:MGI.
DR GO; GO:0033689; P:negative regulation of osteoblast proliferation; ISS:UniProtKB.
DR GO; GO:0017148; P:negative regulation of translation; ISS:UniProtKB.
DR GO; GO:0045071; P:negative regulation of viral genome replication; IMP:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:0032722; P:positive regulation of chemokine production; IMP:UniProtKB.
DR GO; GO:0001819; P:positive regulation of cytokine production; IMP:UniProtKB.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; IMP:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
DR GO; GO:1901532; P:regulation of hematopoietic progenitor cell differentiation; IMP:UniProtKB.
DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; IMP:UniProtKB.
DR GO; GO:1902033; P:regulation of hematopoietic stem cell proliferation; IMP:UniProtKB.
DR GO; GO:1900225; P:regulation of NLRP3 inflammasome complex assembly; IMP:UniProtKB.
DR GO; GO:0035455; P:response to interferon-alpha; ISS:UniProtKB.
DR GO; GO:0032496; P:response to lipopolysaccharide; ISO:MGI.
DR GO; GO:0009636; P:response to toxic substance; ISO:MGI.
DR GO; GO:0009615; P:response to virus; ISS:UniProtKB.
DR GO; GO:0033197; P:response to vitamin E; ISO:MGI.
DR GO; GO:0006412; P:translation; IDA:MGI.
DR CDD; cd19903; DSRM_EIF2AK2_rpt1; 1.
DR CDD; cd19904; DSRM_EIF2AK2_rpt2; 1.
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; Antiviral defense; ATP-binding; Cytoplasm;
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:0000250|UniProtKB:P19525"
FT CHAIN 2..515
FT /note="Interferon-induced, double-stranded RNA-activated
FT protein kinase"
FT /id="PRO_0000085946"
FT DOMAIN 8..76
FT /note="DRBM 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266"
FT DOMAIN 95..162
FT /note="DRBM 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00266"
FT DOMAIN 242..504
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 204..224
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 241..515
FT /note="Interaction with TRAF5"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT ACT_SITE 376
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 248..256
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 271
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 84
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 96
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 157
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 233
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 268
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 409
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 414
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT MOD_RES 419
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT CROSSLNK 68
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT CROSSLNK 154
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15)"
FT /evidence="ECO:0000250|UniProtKB:P19525"
FT CONFLICT 52
FT /note="P -> G (in Ref. 1; AAA40150)"
FT /evidence="ECO:0000305"
FT CONFLICT 60
FT /note="Q -> T (in Ref. 1; AAA40150)"
FT /evidence="ECO:0000305"
FT CONFLICT 87
FT /note="S -> C (in Ref. 1; AAA40150)"
FT /evidence="ECO:0000305"
FT CONFLICT 144
FT /note="T -> I (in Ref. 2; AAA39885)"
FT /evidence="ECO:0000305"
FT CONFLICT 281..282
FT /note="EH -> DR (in Ref. 2; AAA39885)"
FT /evidence="ECO:0000305"
FT CONFLICT 510
FT /note="K -> E (in Ref. 1; AAA40150)"
FT /evidence="ECO:0000305"
FT CONFLICT 512..515
FT /note="RNTC -> KHMLGPF (in Ref. 1; AAA40150)"
FT /evidence="ECO:0000305"
FT HELIX 8..20
FT /evidence="ECO:0007829|PDB:1X49"
FT STRAND 24..33
FT /evidence="ECO:0007829|PDB:1X49"
FT STRAND 35..37
FT /evidence="ECO:0007829|PDB:1X49"
FT STRAND 39..48
FT /evidence="ECO:0007829|PDB:1X49"
FT STRAND 54..58
FT /evidence="ECO:0007829|PDB:1X49"
FT HELIX 59..74
FT /evidence="ECO:0007829|PDB:1X49"
FT HELIX 96..106
FT /evidence="ECO:0007829|PDB:1X48"
FT STRAND 111..115
FT /evidence="ECO:0007829|PDB:1X48"
FT STRAND 119..123
FT /evidence="ECO:0007829|PDB:1X48"
FT STRAND 126..134
FT /evidence="ECO:0007829|PDB:1X48"
FT STRAND 136..144
FT /evidence="ECO:0007829|PDB:1X48"
FT HELIX 145..162
FT /evidence="ECO:0007829|PDB:1X48"
SQ SEQUENCE 515 AA; 58280 MW; 7A116F7D8DB9B847 CRC64;
MASDTPGFYM DKLNKYRQMH GVAITYKELS TSGPPHDRRF TFQVLIDEKE FPEAKGRSKQ
EARNAAAKLA VDILDNENKV DCHTSASEQG LFVGNYIGLV NSFAQKKKLS VNYEQCEPNS
ELPQRFICKC KIGQTMYGTG SGVTKQEAKQ LAAKEAYQKL LKSPPKTAGT SSSVVTSTFS
GFSSSSSMTS NGVSQSAPGS FSSENVFTNG LGENKRKSGV KVSPDDVQRN KYTLDARFNS
DFEDIEEIGL GGFGQVFKAK HRIDGKRYAI KRVKYNTEKA EHEVQALAEL NHVNIVQYHS
CWEGVDYDPE HSMSDTSRYK TRCLFIQMEF CDKGTLEQWM RNRNQSKVDK ALILDLYEQI
VTGVEYIHSK GLIHRDLKPG NIFLVDERHI KIGDFGLATA LENDGKSRTR RTGTLQYMSP
EQLFLKHYGK EVDIFALGLI LAELLHTCFT ESEKIKFFES LRKGDFSNDI FDNKEKSLLK
KLLSEKPKDR PETSEILKTL AEWRNISEKK KRNTC
