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EIF2AK2

GeneName

EIF2AK2

Summary

EIF2AK2, also known as PKR or protein kinase R, is a 62 kDa serine/threonine kinase that plays a crucial role in the cellular response to viral infections and stress. It is predominantly expressed in the cytoplasm and nucleus, and is involved in various biological processes including the antiviral innate immune response, regulation of translation, and the unfolded protein response. EIF2AK2 functions by binding to double-stranded RNA, which activates its kinase activity, leading to the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). This action ultimately inhibits protein synthesis, thereby limiting viral replication. Additionally, it has roles in regulating cytokine production and the MAPK signalling pathways.

Importance

EIF2AK2 is relevant to: - Antiviral therapies, as it is a key player in the host defence against viral infections by modulating translation and immune responses - Cancer research, due to its involvement in regulating apoptosis and cell proliferation - Neurodegenerative diseases, where its activation may contribute to cellular stress responses - Understanding the mechanisms of interferon signalling and its effects on immune regulation

Top Products

For researchers investigating EIF2AK2, we highly recommend the top-selling recombinant antibody, Anti-PKR antibody [YE350] (ab32052). This well-cited antibody has garnered 46 citations, reflecting its reliability and trust within the research community. It has been validated in knockout models and is suitable for a variety of applications, including Western blotting (WB), immunohistochemistry (IHC), immunocytochemistry (ICC), immunoprecipitation (IP), and flow cytometry (FC). This versatility makes it an excellent choice for those seeking consistent and effective detection of EIF2AK2 in their studies.

Abcam Product Citation Summary

The data indicates that the Abcam antibody ab32506 was utilised to study EIF2AK2 in human samples, specifically in the context of HOTAIR's effect on PKR expression. This suggests a potential link between these molecular players in the regulation of cellular processes.

Abcam Product Citation Table

Product Code
Species
Application
Study Context
PMID
ab32506
Human
WB
Effect of HOTAIR on PKR expression
29898032

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).

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).

Involvement in disease

Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome

LEUDEN

An autosomal dominant disorder characterized by global developmental delay apparent in early childhood, cognitive impairment, ataxia, poor or absent speech with dysarthria, hypotonia, hypertonia, extrapyramidal signs, tremor, and abnormal involuntary movements. Affected individuals also exhibit neurological regression in the setting of febrile illness or infection. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities with poor myelination.

None

The disease may be caused by variants affecting the gene represented in this entry.

Dystonia 33

DYT33

A form of dystonia, a disorder defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT33 is a slowly progressive form characterized by onset of focal or generalized dystonia in the first decades of life. Disease manifestations are variable. Some patients show ambulation difficulties, dysarthria, or dysphagia. Some affected individuals may manifest motor delay, lower limb spasticity, and mild developmental delay with intellectual disability. DYT33 penetrance is incomplete. Inheritance can be autosomal dominant or recessive.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

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).

Sequence Similarities

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. GCN2 subfamily.

Tissue Specificity

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.

Cellular localization

Alternative names

PKR, PRKR, EIF2AK2, Eukaryotic translation initiation factor 2-alpha kinase 2, Interferon-inducible RNA-dependent protein kinase, P1/eIF-2A protein kinase, Protein kinase RNA-activated, Tyrosine-protein kinase EIF2AK2, p68 kinase, eIF-2A protein kinase 2, Protein kinase R

swissprot:P19525 entrezGene:5610 omim:176871

Other research areas