InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: EIF2AK2

Summary

InnateDB Protein

IDBP-240183.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

EIF2AK2

Protein Name

eukaryotic translation initiation factor 2-alpha kinase 2

Synonyms

EIF2AK1; PKR; PPP1R83; PRKR;

Species

Homo sapiens

Ensembl Protein

ENSP00000378559

InnateDB Gene

IDBG-44867 (EIF2AK2)

Protein Structure

UniProt Annotation

Function

IFN-induced dsRNA-dependent serine/threonine-protein kinase which plays a key role in the innate immune response to viral infection and is also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation. 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). Inhibits viral replication via phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (EIF2S1), this phosphorylation impairs the recycling of EIF2S1 between successive rounds of initiation leading to inhibition of translation which eventually results in shutdown of cellular and viral protein synthesis. Also phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. 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. 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 proinflammatory 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. Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). 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). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Can trigger apoptosis via FADD-mediated activation of CASP8. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin. {ECO:0000269PubMed:10848580, ECO:0000269PubMed:11836380, ECO:0000269PubMed:15121867, ECO:0000269PubMed:15229216, ECO:0000269PubMed:18835251, ECO:0000269PubMed:19189853, ECO:0000269PubMed:19229320, ECO:0000269PubMed:19507191, ECO:0000269PubMed:19840259, ECO:0000269PubMed:20171114, ECO:0000269PubMed:20395957, ECO:0000269PubMed:20685959, ECO:0000269PubMed:21072047, ECO:0000269PubMed:21123651, ECO:0000269PubMed:21710204, ECO:0000269PubMed:22214662, ECO:0000269PubMed:22381929, ECO:0000269PubMed:22801494, ECO:0000269PubMed:22948139, ECO:0000269PubMed:23084476, ECO:0000269PubMed:23115276, ECO:0000269PubMed:23229543, ECO:0000269PubMed:23372823, ECO:0000269PubMed:23399035}.

Subcellular Localization

Cytoplasm. Nucleus. Cytoplasm, perinuclear region. Note=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.

Disease Associations

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. {ECO:0000269PubMed:21029237, ECO:0000269PubMed:23403623}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 134 experimentally validated interaction(s) in this database.
They are also associated with 3 interaction(s) predicted by orthology.

Experimentally validated
Total	134 [view]
Protein-Protein	120 [view]
Protein-DNA	10 [view]
Protein-RNA	2 [view]
DNA-DNA	2 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	3 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0003725	double-stranded RNA binding
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004694	eukaryotic translation initiation factor 2alpha kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004715	non-membrane spanning protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0008601	protein phosphatase type 2A regulator activity
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0044822	poly(A) RNA binding

Biological Process

GO:0000186	activation of MAPKK activity
GO:0001819	positive regulation of cytokine production
GO:0006351	transcription, DNA-templated
GO:0006468	protein phosphorylation
GO:0008285	negative regulation of cell proliferation
GO:0009615	response to virus
GO:0017148	negative regulation of translation
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0019048	modulation by virus of host morphology or physiology
GO:0019054	modulation by virus of host process
GO:0019058	viral life cycle
GO:0030683	evasion or tolerance by virus of host immune response
GO:0032722	positive regulation of chemokine production
GO:0032874	positive regulation of stress-activated MAPK cascade
GO:0033689	negative regulation of osteoblast proliferation
GO:0035455	response to interferon-alpha
GO:0045071	negative regulation of viral genome replication
GO:0045087	innate immune response (InnateDB)
GO:0046777	protein autophosphorylation
GO:0051092	positive regulation of NF-kappaB transcription factor activity
GO:0051607	defense response to virus
GO:1900225	regulation of NLRP3 inflammasome complex assembly
GO:1901224	positive regulation of NIK/NF-kappaB signaling
GO:1901532	regulation of hematopoietic progenitor cell differentiation
GO:1902033	regulation of hematopoietic stem cell proliferation
GO:1902036	regulation of hematopoietic stem cell differentiation

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0016020	membrane
GO:0048471	perinuclear region of cytoplasm

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR014720 Double-stranded RNA-binding domain
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714
PF00035

PRINTS

PR00109

PIRSF

SMART

SM00220
SM00358
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt