Protein: Interferon-induced, double-stranded RNA-activated protein kinase (EC 2.7.11.1) (Eukaryotic translation initiation factor 2-alpha kinase 2) (eIF-2A protein kinase 2) (Interferon-inducible RNA-dependent protein kinase) (P1/eIF-2A protein kinase) (Protein kinase RNA-activated) (PKR) (Protein kinase R) (Serine/threonine-protein kinase TIK) (Tyrosine-protein kinase EIF2AK2) (EC 2.7.10.2) (p68 kinase) (Q03963)
Organism: Mus musculus (Mouse)
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. 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. 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). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, and IRS1. 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. 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. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin.
Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:P19525}. Nucleus {ECO:0000250|UniProtKB:P19525}. Cytoplasm, perinuclear region {ECO:0000250|UniProtKB:P19525}.
Interaction partners:
- Eukaryotic translation initiation factor 2 subunit 1
- Ubiquitin-like protein ISG15
- Antiviral innate immune response effector IFIT1
- DnaJ homolog subfamily C member 3
- Insulin receptor substrate 1
- Antiviral innate immune response receptor RIG-I
- Receptor-interacting serine/threonine-protein kinase 1
- Inhibitor of nuclear factor kappa-B kinase subunit alpha
- Inhibitor of nuclear factor kappa-B kinase subunit beta
- Interferon-induced helicase C domain-containing protein 1
Sequence:
MASDTPGFYMDKLNKYRQMHGVAITYKELSTSGPPHDRRFTFQVLIDEKEFPEAKGRSKQEARNAAAKLAVDILDNENKVDCHTSASEQGLFVGNYIGLVNSFAQKKKLSVNYEQCEPNSELPQRFICKCKIGQTMYGTGSGVTKQEAKQLAAKEAYQKLLKSPPKTAGTSSSVVTSTFSGFSSSSSMTSNGVSQSAPGSFSSENVFTNGLGENKRKSGVKVSPDDVQRNKYTLDARFNSDFEDIEEIGLGGFGQVFKAKHRIDGKRYAIKRVKYNTEKAEHEVQALAELNHVNIVQYHSCWEGVDYDPEHSMSDTSRYKTRCLFIQMEFCDKGTLEQWMRNRNQSKVDKALILDLYEQIVTGVEYIHSKGLIHRDLKPGNIFLVDERHIKIGDFGLATALENDGKSRTRRTGTLQYMSPEQLFLKHYGKEVDIFALGLILAELLHTCFTESEKIKFFESLRKGDFSNDIFDNKEKSLLKKLLSEKPKDRPETSEILKTLAEWRNISEKKKRNTC