Query author contributions in Reactome
Reactome depends on collaboration between our curation team and outside experts to assemble and peer-review its pathway modules. The integration of ORCID within Reactome enables us to meet a key challenge with authoring, curating and reviewing biological information by incentivizing and crediting the external experts that contribute their expertise and time to the Reactome curation process. More information is available at ORCID and Reactome.
If you have an ORCID ID that is not listed on this page, please forward this information to us and we will update your Reactome pathway records.
Details on Person UniProt:P19525 EIF2AK2
| Class:Id | ReferenceGeneProduct:54078 |
|---|---|
| _chainChangeLog | initiator methionine:1 added on Fri February 6 2015;chain:2-551 added on Fri February 6 2015;initiator methionine:1 for 54078 removed on Fri Nov 03 2023;initiator methionine: for 54078 added on Fri Nov 03 2023;initiator methionine: for 54078 removed on Fri Aug 15 2025;initiator methionine:1 for 54078 added on Fri Aug 15 2025 |
| _displayName | UniProt:P19525 EIF2AK2 |
| _timestamp | 2026-02-20 23:04:57 |
| chain | initiator methionine:1 chain:2-551 |
| checksum | 815AD83ACAB45DA3 |
| comment | 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:18835251, PubMed:19189853, PubMed:19507191, PubMed:21072047, PubMed:21123651, PubMed:22381929, PubMed:22948139, PubMed:23229543). 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:19189853, PubMed:21123651, PubMed:22948139, PubMed:23229543). Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1) (PubMed:11836380, PubMed:19189853, PubMed:19840259, PubMed:20171114, PubMed:21710204, PubMed:23115276, PubMed:23399035). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11 (PubMed:11836380, PubMed:19229320, PubMed:22214662). 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 proteasomal degradation (PubMed:20395957). 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:22948139, PubMed:23084476, PubMed:23372823). 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 (PubMed:10848580, PubMed:15121867, PubMed:15229216). Can act as both a positive and negative regulator of the insulin signaling pathway (ISP) (PubMed:20685959). 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) (PubMed:20685959). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes (PubMed:22801494). Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin (By similarity).CATALYTIC ACTIVITY L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+)CATALYTIC ACTIVITY L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+)CATALYTIC ACTIVITY L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+)COFACTOR Initially produced in an inactive form and is activated by binding to viral dsRNA, which causes dimerization and autophosphorylation in the activation loop and stimulation of function. ISGylation can activate it in the absence of viral infection. Can also be activated by heparin, pro-inflammatory stimuli, growth factors, cytokines, oxidative stress and the cellular protein PRKRA. Activity is markedly stimulated by manganese ions. Activation is blocked by the viral components HIV-1 Tat protein and large amounts of HIV-1 trans-activation response (TAR) RNA element as well as by the cellular proteins TARBP2, DUS2L, NPM1, NCK1 and ADAR. Down-regulated by Toscana virus (TOS) and Rift valley fever virus (RVFV) NSS which promote its proteasomal degradation. Inhibited by vaccinia virus protein E3, probably via dsRNA sequestering.SUBUNIT Homodimer (PubMed:16179258, PubMed:31246429). Interacts with STRBP (By similarity). Interacts with DNAJC3. Forms a complex with FANCA, FANCC, FANCG and HSP70. Interacts with ADAR/ADAR1. Interacts with IRS1 (By similarity). The inactive form interacts with NCK1 and GSN. Interacts (via the kinase catalytic domain) with STAT3 (via SH2 domain), TRAF2 (C-terminus), TRAF5 (C-terminus) and TRAF6 (C-terminus). Interacts with MAP2K6, IKBKB/IKKB, NPM1, TARBP2, NLRP1, NLRP3, NLRC4 and AIM2. Interacts (via DRBM 1 domain) with DUS2L (via DRBM domain). Interacts with DHX9 (via N-terminus) and this interaction is dependent upon activation of the kinase. Interacts with EIF2S1/EIF-2ALPHA; this interaction induces a conformational change in EIF2S1 and its phosphorylation by EIF2AK2 (PubMed:16179258). Interacts with MBIP; the interaction is direct and leads to inhibition of EIF2AK2 self-activating autophosphorylation (PubMed:26705305). Interacts with the molybdopterin synthase complex subunit MOCS2B; the interaction is direct and enhances the interaction between EIF2AK2 and MBIP (PubMed:26705305).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus (HCMV) TRS1; this interaction retains EIF2AK2 to the nucleus and prevents its activation.SUBUNIT (Microbial infection) Interacts with vaccinia virus protein K3 (K3L); this interaction inhibits EIF2AK2.SUBUNIT (Microbial infection) Interacts with human herpes simplex virus 1 (HHV-1) protein US11 in an RNA-dependent manner.SUBUNIT (Microbial infection) The inactive form interacts with Toscana virus (TOS) NSS.SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein v-IRF2; this interaction inhibits EIF2AK2 activation.SUBUNIT (Microbial infection) Interacts with vaccinia protein E3.SUBUNIT (Microbial infection) Interacts (via N-terminus) with Hepatitis C virus (HCV) mature core protein (via N-terminus); this interaction induces the autophosphorylation of EIF2AK2.SUBUNIT (Microbial infection) Interacts with Hepatitis C virus (HCV) non-structural protein 5A (NS5A); this interaction leads to disruption of EIF2AK2 dimerization by NS5A.SUBUNIT (Microbial infection) Interacts with Hepatitis C virus (HCV) envelope glycoprotein E2; this interaction inhibits EIF2AK2 and blocks its inhibitory effect on protein synthesis and cell growth.SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) nucleoprotein; this interaction inhibits EIF2AK2 phosphorylation of EIF2S1 and blocks EIF2AK2-mediated translation shutoff.SUBUNIT (Microbial infection) Interacts with human herpesvirus 8 protein MTA/ORF57; this interaction inhibits stress granule formation.INTERACTION Nuclear localization is elevated in acute leukemia, myelodysplastic syndrome (MDS), melanoma, breast, colon, prostate and lung cancer patient samples or cell lines as well as neurocytes from advanced Creutzfeldt-Jakob disease patients.ALTERNATIVE PRODUCTS Highly expressed in thymus, spleen and bone marrow compared to non-hematopoietic tissues such as small intestine, liver, or kidney tissues. Colocalizes with GSK3B and TAU in the Alzheimer disease (AD) brain. Elevated levels seen in breast and colon carcinomas, and which correlates with tumor progression and invasiveness or risk of progression.INDUCTION By type I interferons.DOMAIN Contains 2 dsRNA-binding domain (DRBM) (PubMed:9736623). The N-terminus contains the catalytic domain dimerization. The C-terminus binds EIF2S1/EIF2-alpha (PubMed:16179258).PTM Autophosphorylated on several Ser, Thr and Tyr residues. Autophosphorylation of Thr-451 is dependent on Thr-446 and is stimulated by dsRNA binding and dimerization. Autophosphorylation apparently leads to the activation of the kinase. Tyrosine autophosphorylation is essential for efficient dsRNA-binding, dimerization, and kinase activation. Autophosphorylation is inhibited by the concerted action of ATAC complex subunit MBIP and molybdopterin synthase complex subunit MOCS2B (PubMed:26705305).DISEASE The disease may be caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily. |
| description | recommendedName: Interferon-induced, double-stranded RNA-activated protein kinase ecNumber: 2.7.11.1 alternativeName: Eukaryotic translation initiation factor 2-alpha kinase 2 shortName: eIF-2A protein kinase 2 alternativeName: Interferon-inducible RNA-dependent protein kinase alternativeName: P1/eIF-2A protein kinase alternativeName: Protein kinase RNA-activated shortName: PKR shortName evidence="68"Protein kinase R alternativeName: Tyrosine-protein kinase EIF2AK2 ecNumber: 2.7.10.2 alternativeName: p68 kinase |
| geneName | EIF2AK2 PKR PRKR |
| identifier | P19525 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Alternative splicing Antiviral defense ATP-binding Cytoplasm Direct protein sequencing Disease variant Dystonia Host-virus interaction Immunity Innate immunity Isopeptide bond Kinase Magnesium Nucleotide-binding Nucleus Phosphoprotein Proteomics identification Reference proteome Repeat RNA-binding Serine/threonine-protein kinase Transcription Transcription regulation Transferase Tyrosine-protein kinase Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9841277] Weiser, Joel [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9909836] Weiser, Joel, 2024-05-14 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | EIF2AK2 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8957931] ENSEMBL:ENSG00000055332 EIF2AK2 [Homo sapiens] |
| secondaryIdentifier | E2AK2_HUMAN A8K3P0 D6W584 E9PC80 Q52M43 Q7Z6F6 Q9UIR4 |
| sequenceLength | 551 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:8967385] UniProt:P19525-1 EIF2AK2 [Homo sapiens] [ReferenceIsoform:8967386] UniProt:P19525-2 EIF2AK2 [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:168673] p-EIF2AK2 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:168699] EIF2AK2 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:8957528] EIF2AK2 [extracellular region] [Homo sapiens] [EntityWithAccessionedSequence:9833637] EIF2AK2 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:9833834] p-EIF2AK2 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9833968] ISG15-EIF2AK2 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9834829] SUMO-EIF2AK2 [cytosol] [Homo sapiens] [EntityWithAccessionedSequence:9836332] p-EIF2AK2 [nucleoplasm] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:168436] phosphorylated residue at unknown position [ModifiedResidue:9833814] O4'-phospho-L-tyrosine at 293 [ModifiedResidue:9833816] O-phospho-L-serine at 242 [ModifiedResidue:9833819] O4'-phospho-L-tyrosine at 101 [ModifiedResidue:9833823] O-phospho-L-threonine at 446 [ModifiedResidue:9833825] O-phospho-L-threonine at 89 [ModifiedResidue:9833831] O-phospho-L-threonine at 88 [ModifiedResidue:9833835] O-phospho-L-threonine at 258 [ModifiedResidue:9833840] O-phospho-L-threonine at 90 [ModifiedResidue:9833849] O4'-phospho-L-tyrosine at 162 |
| [Change default viewing format] | |
No pathways have been reviewed or authored by UniProt:P19525 EIF2AK2 (54078)
