ID  Q03963;
PN  Interferon-induced, double-stranded RNA-activated protein kinase;
GN  Eif2ak2;
OS  10090;
SL  Nucleus Position: SL-0198;
SL  Comments: Cytoplasm {ECO:0000250|UniProtKB:P19525}. Nucleus {ECO:0000250|UniProtKB:P19525}. Cytoplasm, perinuclear region {ECO:0000250|UniProtKB:P19525}.
DR  UNIPROT: Q03963;
DR  UNIPROT: Q61742;
DR  UNIPROT: Q62026;
DR  PDB: 1X48;
DR  PDB: 1X49;
DR  Pfam: PF00035;
DR  Pfam: PF00069;
DR  PROSITE: PS50137;
DR  PROSITE: PS00107;
DR  PROSITE: PS50011;
DR  PROSITE: PS00108;
DE  Function: IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection (PubMed:20038207, PubMed:20478537, PubMed:21123651). Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2-alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4 (PubMed:21123651, PubMed:20631127). Exerts its antiviral activity on a wide range of DNA and RNA viruses including west nile virus (WNV), sindbis virus (SV), foot-and-mouth virus (FMDV), semliki Forest virus (SFV) and lymphocytic choriomeningitis virus (LCMV) (PubMed:19264662, PubMed:20585572, PubMed:20631127, PubMed:21994357). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, and IRS1 (PubMed:19229320, PubMed:23403623). In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation (By similarity). Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF- kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding pro-inflammatory cytokines and IFNs (PubMed:22948222, PubMed:23392680). Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6 (By similarity). Can act as both a positive and negative regulator of the insulin signaling pathway (ISP) (By similarity). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2) (By similarity). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes (PubMed:22801494, PubMed:23401008). Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin (PubMed:22633459). {ECO:0000250|UniProtKB:P19525, ECO:0000269|PubMed:19229320, ECO:0000269|PubMed:19264662, ECO:0000269|PubMed:20038207, ECO:0000269|PubMed:20478537, ECO:0000269|PubMed:20585572, ECO:0000269|PubMed:20631127, ECO:0000269|PubMed:21123651, ECO:0000269|PubMed:21994357, ECO:0000269|PubMed:22633459, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:22948222, ECO:0000269|PubMed:23392680, ECO:0000269|PubMed:23401008, ECO:0000269|PubMed:23403623}.
DE  Reference Proteome: Yes;
DE  Interaction: P35569; IntAct: EBI-2603482; Score: 0.40
DE  Interaction: P35570; IntAct: EBI-2603524; Score: 0.44
DE  Interaction: Q8R4B8; IntAct: EBI-15999088; Score: 0.52
DE  Interaction: Q9EPB4; IntAct: EBI-15999182; Score: 0.40
GO  GO:0005737;
GO  GO:0005829;
GO  GO:0005634;
GO  GO:0048471;
GO  GO:0005524;
GO  GO:0003725;
GO  GO:0004694;
GO  GO:0042802;
GO  GO:0004715;
GO  GO:0004672;
GO  GO:0106310;
GO  GO:0034198;
GO  GO:0051607;
GO  GO:0030968;
GO  GO:0045087;
GO  GO:0043066;
GO  GO:0033689;
GO  GO:0017148;
GO  GO:0045071;
GO  GO:0043065;
GO  GO:0032722;
GO  GO:0001819;
GO  GO:0043410;
GO  GO:0051092;
GO  GO:1901224;
GO  GO:0032874;
GO  GO:0046777;
GO  GO:0006468;
GO  GO:1901532;
GO  GO:1902036;
GO  GO:1902033;
GO  GO:1900225;
GO  GO:0035455;
GO  GO:0032496;
GO  GO:0009636;
GO  GO:0009615;
GO  GO:0033197;
GO  GO:0006412;
TP  Membrane Topology: Unknown; Source: UniProt - Sequence Analysis;
SQ  MASDTPGFYMDKLNKYRQMHGVAITYKELSTSGPPHDRRFTFQVLIDEKEFPEAKGRSKQEARNAAAKLAVDILDNENKV
SQ  DCHTSASEQGLFVGNYIGLVNSFAQKKKLSVNYEQCEPNSELPQRFICKCKIGQTMYGTGSGVTKQEAKQLAAKEAYQKL
SQ  LKSPPKTAGTSSSVVTSTFSGFSSSSSMTSNGVSQSAPGSFSSENVFTNGLGENKRKSGVKVSPDDVQRNKYTLDARFNS
SQ  DFEDIEEIGLGGFGQVFKAKHRIDGKRYAIKRVKYNTEKAEHEVQALAELNHVNIVQYHSCWEGVDYDPEHSMSDTSRYK
SQ  TRCLFIQMEFCDKGTLEQWMRNRNQSKVDKALILDLYEQIVTGVEYIHSKGLIHRDLKPGNIFLVDERHIKIGDFGLATA
SQ  LENDGKSRTRRTGTLQYMSPEQLFLKHYGKEVDIFALGLILAELLHTCFTESEKIKFFESLRKGDFSNDIFDNKEKSLLK
SQ  KLLSEKPKDRPETSEILKTLAEWRNISEKKKRNTC
//