EIF2AK2 eukaryotic translation initiation factor 2 alpha kinase 2 [Homo sapiens (human)] - Gene

Summary

Official Symbol: EIF2AK2provided by HGNC
Official Full Name: eukaryotic translation initiation factor 2 alpha kinase 2provided by HGNC
Primary source: HGNC:HGNC:9437
See related: Ensembl:ENSG00000055332 MIM:176871; AllianceGenome:HGNC:9437
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: PKR; PRKR; DYT33; LEUDEN; EIF2AK1; PPP1R83
Summary: The protein encoded by this gene is a serine/threonine protein kinase that is activated by autophosphorylation after binding to dsRNA. The activated form of the encoded protein can phosphorylate translation initiation factor EIF2S1, which in turn inhibits protein synthesis. This protein is also activated by manganese ions and heparin. The encoded protein plays an important role in the innate immune response against multiple DNA and RNA viruses. [provided by RefSeq, Jul 2021]
Annotation information: Note: This gene has been reviewed for its involvement in coronavirus biology, and is involved in immune response or antiviral activity.
Expression: Ubiquitous expression in bone marrow (RPKM 8.7), brain (RPKM 6.4) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 2p22.2

Exon count:: 17

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	2	NC_000002.12 (37099210..37156980, complement)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	2	NC_060926.1 (37106342..37164108, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (37326353..37384123, complement)

Chromosome 2 - NC_000002.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Involvement of Protein Kinase R in Double-Stranded RNA-Induced Proteasomal Degradation of Hypoxia Inducible Factor-1alpha.
Title: Involvement of Protein Kinase R in Double-Stranded RNA-Induced Proteasomal Degradation of Hypoxia Inducible Factor-1α.
Chemotherapy-Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA-Mediated PKR Activation.
Title: Chemotherapy-Induced Senescence Reprogramming Promotes Nasopharyngeal Carcinoma Metastasis by circRNA-Mediated PKR Activation.
The role of protein kinase R in placental inflammation, mtUPR and apoptosis.
Title: The role of protein kinase R in placental inflammation, mtUPR and apoptosis.
Structural study of novel vaccinia virus E3L and dsRNA-dependent protein kinase complex.
Title: Structural study of novel vaccinia virus E3L and dsRNA-dependent protein kinase complex.
The double-stranded RNA-dependent protein kinase PKR negatively regulates the protein expression of IFN-beta induced by RIG-I signaling.
Title: The double-stranded RNA-dependent protein kinase PKR negatively regulates the protein expression of IFN-β induced by RIG-I signaling.
YTHDF3 Facilitates eIF2AK2 and eIF3A Recruitment on mRNAs to Regulate Translational Processes in Oxaliplatin-Resistant Colorectal Cancer.
Title: YTHDF3 Facilitates eIF2AK2 and eIF3A Recruitment on mRNAs to Regulate Translational Processes in Oxaliplatin-Resistant Colorectal Cancer.
The A150V Polymorphism of Genotype 3 Hepatitis C Virus Polymerase Inhibits Interferon Alfa by Suppressing Protein Kinase R Activation.
Title: The A150V Polymorphism of Genotype 3 Hepatitis C Virus Polymerase Inhibits Interferon Alfa by Suppressing Protein Kinase R Activation.
Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24.
Title: Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24.
The alternative initiation factor eIF2A plays key role in RAN translation of myotonic dystrophy type 2 CCUG*CAGG repeats.
Title: The alternative initiation factor eIF2A plays key role in RAN translation of myotonic dystrophy type 2 CCUG•CAGG repeats.
Mitophagy antagonism by ZIKV reveals Ajuba as a regulator of PINK1 signaling, PKR-dependent inflammation, and viral invasion of tissues.
Title: Mitophagy antagonism by ZIKV reveals Ajuba as a regulator of PINK1 signaling, PKR-dependent inflammation, and viral invasion of tissues.

Submit: New GeneRIF Correction See all GeneRIFs (262)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Dystonia 33 MedGen: C5562054 OMIM: 619687 GeneReviews: Not available	not available
Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome MedGen: C5394367 OMIM: 618877 GeneReviews: Not available	Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp120	env	Overexpression of ADAR1 increases the levels of gp120, p24, and Nef in HIV-1 producer cells, which requires inhibition of the RNA-activated protein kinase PKR	PubMed
	env	Inactivation of PKR has an inhibitory effect on gp120-induced caspase-3 activation	PubMed
	env	HIV-1 gp120 induces activation of PKR and its translocation from cytoplasm to nucleus in neuronal cell lines	PubMed
Envelope surface glycoprotein gp160, precursor	env	Activation of PKR decreases HIV-1 Env expression and knockdown of PKR expression increases intracellular HIV-1 Env expression in human and murine cell lines	PubMed
Nef	nef	The small molecule PKR inhibitor C16 inhibits the IFITM3-induced suppression of HIV-1 Gag, Vif, and Nef protein expression	PubMed
	nef	Overexpression of ADAR1 increases the levels of gp120, p24, and Nef in HIV-1 producer cells, which requires inhibition of the RNA-activated protein kinase PKR	PubMed
Pr55(Gag)	gag	The small molecule PKR inhibitor C16 inhibits the IFITM3-induced suppression of HIV-1 Gag, Vif, and Nef protein expression	PubMed
	gag	HIV-1 Gag is identified to have a physical interaction with eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) in human HEK293 and/or Jurkat cell lines by using affinity tagging and purification mass spectrometry analyses	PubMed
Tat	tat	HIV-1 Tat, specifically amino acids 49-57, increases activation of PKR in Leishmania-infected macrophages	PubMed
	tat	HIV-1 Tat increases expression of EIF2AK2 (PKR) in Leishmania-infected macrophages	PubMed
	tat	PKR directly interacts with HIV-1 Tat and phosphorylates the first exon of Tat exclusively at five Ser/Thr residues (T23, T40, S46, S62, and S68), which inhibits Tat-mediated provirus transcription	PubMed
	tat	PKR-mediated Tat phosphorylation inhibits Tat nuclear localization, and disrupts Tat binding to HIV-1 TAR RNA and interaction with cyclin T1 in HeLa cells	PubMed
	tat	Mutations in HIV-1 Tat that prevent Tat phosphorylation by PKR result in an up to 4-fold decrease in HIV-1 LTR transactivation by Tat	PubMed
	tat	HIV-1 Tat-induction of IL-10 dysregulation is associated with PKR activation in primary blood monocytes	PubMed
	tat	Microarray analysis indicates HIV-1 Tat upregulates the interferon-responsive gene expression of many proteins, including PKR, in immature dendritic cells, an effect that likely facilitates the expansion of HIV-1 infection	PubMed
	tat	PKR enhances HIV-1 Tat-mediated activation of NF-kappaB activation and transcriptional induction of the HIV-1 LTR promoter in the murine HL3T1 cell line	PubMed
	tat	HIV-1 Tat downregulates the steady-state amount of p68 kinase (PKR) in interferon-treated HeLa cells stably expressing Tat	PubMed
	tat	HIV-1 Tat inhibits the activation, activity and autophosphorylation of PKR, suggesting a potential mechanism by which HIV could suppress the interferon system	PubMed
	tat	Binding of HIV-1 Tat to PKR has been mapped to residues 40-58 of Tat, overlapping the hydrophobic core and basic region of Tat	PubMed
	tat	HIV-1 Tat is phosphorylated by PKR on serine 62, threonine 64 and serine 68	PubMed
	tat	HIV-1 Tat interacts with interferon-inducible enzymes 2-5A synthetase and dsRNA-dependent protein kinase to influence the rate of translation and protein synthesis in vitro	PubMed
Vif	vif	The small molecule PKR inhibitor C16 inhibits the IFITM3-induced suppression of HIV-1 Gag, Vif, and Nef protein expression	PubMed
Vpu	vpu	The expression of eukaryotic translation initiation factor 2-alpha kinase 2 is enhanced in Vpu-deficient HIV-1-infected cells as compared to that in wild-type-infected cells	PubMed
capsid	gag	Overexpression of ADAR1 increases the levels of gp120, p24, and Nef in HIV-1 producer cells, which requires inhibition of the RNA-activated protein kinase PKR	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH103558 (e-PCR)
- UniSTS:97883

PRKR_2017 (e-PCR)
- UniSTS:280928

STS-U50648 (e-PCR)
- UniSTS:76899

D10S16 (e-PCR)
- UniSTS:155756

PMC355900P1 (e-PCR)
- UniSTS:273263

SGC31475 (e-PCR)
- UniSTS:62094

RH93202 (e-PCR)
- UniSTS:93085

csnpprkr-pcr12-1 (e-PCR)
- UniSTS:243108

RH69133 (e-PCR)
- UniSTS:41193

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables ATP binding	IEA Inferred from Electronic Annotation more info
enables RNA binding	HDA more info	PubMed
enables double-stranded RNA binding	IDA Inferred from Direct Assay more info	PubMed
enables eukaryotic translation initiation factor 2alpha kinase activity	IBA Inferred from Biological aspect of Ancestor more info
enables eukaryotic translation initiation factor 2alpha kinase activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables kinase activity	IDA Inferred from Direct Assay more info	PubMed
enables non-membrane spanning protein tyrosine kinase activity	IEA Inferred from Electronic Annotation more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein kinase activity	IDA Inferred from Direct Assay more info	PubMed
enables protein kinase activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables protein phosphatase regulator activity	TAS Traceable Author Statement more info	PubMed
enables protein serine kinase activity	IEA Inferred from Electronic Annotation more info
enables protein serine/threonine kinase activity	TAS Traceable Author Statement more info	PubMed

Process	Evidence Code	Pubs
involved_in antiviral innate immune response	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular response to amino acid starvation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in defense response to virus	IEP Inferred from Expression Pattern more info	PubMed
involved_in eiF2alpha phosphorylation in response to endoplasmic reticulum stress	IBA Inferred from Biological aspect of Ancestor more info
involved_in endoplasmic reticulum unfolded protein response	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of cell population proliferation	TAS Traceable Author Statement more info	PubMed
involved_in negative regulation of osteoblast proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of translation	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of translation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of viral genome replication	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of MAPK cascade	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of NF-kappaB transcription factor activity	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of chemokine production	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of cytokine production	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of non-canonical NF-kappaB signal transduction	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of stress-activated MAPK cascade	ISS Inferred from Sequence or Structural Similarity more info
involved_in protein autophosphorylation	IDA Inferred from Direct Assay more info	PubMed
involved_in protein autophosphorylation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in protein phosphorylation	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of NLRP3 inflammasome complex assembly	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of hematopoietic progenitor cell differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of hematopoietic stem cell differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of hematopoietic stem cell proliferation	ISS Inferred from Sequence or Structural Similarity more info
involved_in response to interferon-alpha	IDA Inferred from Direct Assay more info	PubMed
involved_in response to virus	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in translation	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
is_active_in cytoplasm	IBA Inferred from Biological aspect of Ancestor more info
is_active_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	IDA Inferred from Direct Assay more info
located_in cytosol	TAS Traceable Author Statement more info
located_in membrane	HDA more info	PubMed
located_in nucleoplasm	TAS Traceable Author Statement more info
is_active_in nucleus	IBA Inferred from Biological aspect of Ancestor more info
located_in perinuclear region of cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in ribosome	TAS Traceable Author Statement more info	PubMed

General protein information

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Preferred Names: interferon-induced, double-stranded RNA-activated protein kinase

Names: P1/eIF-2A protein kinase; double stranded RNA activated protein kinase; eIF-2A protein kinase 2; interferon-inducible elF2alpha kinase; p68 kinase; protein kinase R; protein kinase RNA-regulated; protein kinase, interferon-inducible double stranded RNA dependent; protein phosphatase 1, regulatory subunit 83; tyrosine-protein kinase EIF2AK2

NP_001129123.1

EC 2.7.10.2

EC 2.7.11.1

NP_001129124.1

EC 2.7.10.2

EC 2.7.11.1

NP_002750.1

EC 2.7.10.2

EC 2.7.11.1

XP_011531289.1

EC 2.7.10.2

EC 2.7.11.1

XP_047301071.1

EC 2.7.10.2

EC 2.7.11.1

XP_047301072.1

EC 2.7.10.2

EC 2.7.11.1

XP_054198993.1

EC 2.7.10.2

EC 2.7.11.1

XP_054198994.1

EC 2.7.10.2

EC 2.7.11.1

XP_054198995.1

EC 2.7.10.2

EC 2.7.11.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_030351.2 RefSeqGene

Range

5000..62770

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001135651.3 → NP_001129123.1 interferon-induced, double-stranded RNA-activated protein kinase isoform a

See identical proteins and their annotated locations for NP_001129123.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) uses a different splice site in the 5' UTR, compared to variant 1. Variants 1 and 2 both encode the same protein (isoform a).

Source sequence(s)

AC007899, BC040851, BU687340

Consensus CDS

CCDS1786.1

UniProtKB/Swiss-Prot

A8K3P0, D6W584, E9PC80, P19525, Q52M43, Q7Z6F6, Q9UIR4

UniProtKB/TrEMBL

B7ZKK7

Related

ENSP00000233057.4, ENST00000233057.9

Conserved Domains (2) summary

smart00358
Location:101 → 166

DSRM; Double-stranded RNA binding motif

cd14047
Location:260 → 536

STKc_EIF2AK2_PKR; Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 2 or Protein Kinase regulated by RNA
NM_001135652.2 → NP_001129124.1 interferon-induced, double-stranded RNA-activated protein kinase isoform b

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (b) has the same N- and C-termini but is shorter compared to isoform a. The 5' UTR splice pattern of this transcript has not been determined.

Source sequence(s)

AC007899, BC101475, BU687340

Consensus CDS

CCDS46259.1

UniProtKB/TrEMBL

B7ZKK7

Related

ENSP00000385014.1, ENST00000405334.5

Conserved Domains (3) summary

smart00220
Location:252 → 493

S_TKc; Serine/Threonine protein kinases, catalytic domain

smart00358
Location:101 → 166

DSRM; Double-stranded RNA binding motif

cl21453
Location:262 → 495

PKc_like; Protein Kinases, catalytic domain
NM_002759.4 → NP_002750.1 interferon-induced, double-stranded RNA-activated protein kinase isoform a

See identical proteins and their annotated locations for NP_002750.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript. Variants 1 and 2 both encode the same protein (isoform a).

Source sequence(s)

AC007899, BC040851, BU687340

Consensus CDS

CCDS1786.1

UniProtKB/Swiss-Prot

A8K3P0, D6W584, E9PC80, P19525, Q52M43, Q7Z6F6, Q9UIR4

UniProtKB/TrEMBL

B7ZKK7

Related

ENSP00000378559.2, ENST00000395127.6

Conserved Domains (2) summary

smart00358
Location:101 → 166

DSRM; Double-stranded RNA binding motif

cd14047
Location:260 → 536

STKc_EIF2AK2_PKR; Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 2 or Protein Kinase regulated by RNA

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000002.12 Reference GRCh38.p14 Primary Assembly

Range

37099210..37156980 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_047445116.1 → XP_047301072.1 interferon-induced, double-stranded RNA-activated protein kinase isoform X2

UniProtKB/TrEMBL

A0A7P0Z4M0

Related

ENSP00000506455.1, ENST00000679979.1
XM_011532987.3 → XP_011531289.1 interferon-induced, double-stranded RNA-activated protein kinase isoform X1

See identical proteins and their annotated locations for XP_011531289.1

UniProtKB/Swiss-Prot

A8K3P0, D6W584, E9PC80, P19525, Q52M43, Q7Z6F6, Q9UIR4

UniProtKB/TrEMBL

B7ZKK7

Related

ENSP00000505772.1, ENST00000681507.1

Conserved Domains (2) summary

smart00358
Location:101 → 166

DSRM; Double-stranded RNA binding motif

cd14047
Location:260 → 536

STKc_EIF2AK2_PKR; Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 2 or Protein Kinase regulated by RNA
XM_047445115.1 → XP_047301071.1 interferon-induced, double-stranded RNA-activated protein kinase isoform X2

UniProtKB/TrEMBL

A0A7P0Z4M0

Alternate T2T-CHM13v2.0

Genomic

NC_060926.1 Alternate T2T-CHM13v2.0

Range

37106342..37164108 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054343020.1 → XP_054198995.1 interferon-induced, double-stranded RNA-activated protein kinase isoform X2

UniProtKB/TrEMBL

A0A7P0Z4M0
XM_054343018.1 → XP_054198993.1 interferon-induced, double-stranded RNA-activated protein kinase isoform X1

UniProtKB/Swiss-Prot

A8K3P0, D6W584, E9PC80, P19525, Q52M43, Q7Z6F6, Q9UIR4
XM_054343019.1 → XP_054198994.1 interferon-induced, double-stranded RNA-activated protein kinase isoform X2

UniProtKB/TrEMBL

A0A7P0Z4M0