EIF2AK3 eukaryotic translation initiation factor 2-alpha kinase 3 [Homo sapiens (human)] - Gene

Summary

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Official Symbol: EIF2AK3provided by HGNC
Official Full Name: eukaryotic translation initiation factor 2-alpha kinase 3provided by HGNC
Primary source: HGNC:3255
See related: Ensembl:ENSG00000172071; HPRD:04942; MIM:604032; Vega:OTTHUMG00000155046
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: PEK; WRS; PERK
Summary: The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins. Mutations in this gene are associated with Wolcott-Rallison syndrome. [provided by RefSeq, Jan 2010]

Genomic context

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Location :: 2p12

Sequence :: Chromosome: 2; NC_000002.11 (88856259..88927094, complement)

See EIF2AK3 in Epigenomics, MapViewer

Chromosome 2 - NC_000002.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

Bibliography

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GeneRIFs: Gene References Into Functions What's a GeneRIF?

ER stress activates NF-kappaB by integrating functions of basal IKK activity, IRE1 and PERK.
Title: ER stress activates NF-κB by integrating functions of basal IKK activity, IRE1 and PERK.
PERK plays a critical role in information processing and cognitive function and that modulation of eIF2alpha phosphorylation and ATF4 expression.
Title: Brain-specific disruption of the eIF2α kinase PERK decreases ATF4 expression and impairs behavioral flexibility.
PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1alpha-mediated unfolded protein response.
Title: PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1α-mediated unfolded protein response.
one of three endoplasmic reticulum transmembrane protein sensors that signals the unfolded protein response [review]
Title: Unfolded protein response.
results show that the PERK/ATF4 arm of UPR mediates the angiogenic switch and is a potential target for antiangiogenic cancer therapy.
Title: The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway.
This study indicates that selectively activating ATF6 or PERK prevents mutant rhodopsin from accumulating in retinal cells.
Title: Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulation.
Saturated fatty acid-induced ER stress and apoptosis in these human liver cells were enacted through the PERK/ATF4/CHOP signaling pathway.
Title: Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway.
Endoplasmic reticulum stress sensitizes cells to TRAIL through down-regulation of FLIP and Mcl-1 and PERK-dependent up-regulation of TRAIL-R2.
Title: ER stress sensitizes cells to TRAIL through down-regulation of FLIP and Mcl-1 and PERK-dependent up-regulation of TRAIL-R2.
Common nonsynonymous sequence variants in EIF2AK3 have a modest effect on endoplasmic reticulum stress response.
Title: A functional haplotype in EIF2AK3, an ER stress sensor, is associated with lower bone mineral density.
ubtilase cytotoxin -induced ER stress is caused by BiP cleavage, leading to PERK activation, not by accumulation of ubiquitinated proteins, which undergo PERK-dependent degradation via the ubiquitin-proteasome system.
Title: Regulation of subtilase cytotoxin-induced cell death by an RNA-dependent protein kinase-like endoplasmic reticulum kinase-dependent proteasome pathway in HeLa cells.

Submit: New GeneRIF Correction See all (47)

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

NHGRI GWAS Catalog

Hundreds of variants clustered in genomic loci and biological pathways affect human height.

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.

HIV-1 protein interactions

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Protein	Gene	Interaction	Pubs
Env, gp160, envelope glycoprotein	env	Knockdown of PERK expression increases intracellular HIV-1 Env expression in human and murine cell lines	PubMed
Tat, p14	tat	Exposure of human umbilical vein endothelial cells to HIV-1 Tat causes broad activation of the unfolded-protein response in ER with phosphorylation of PERK, eIF2alpha, and JNK and induction of Grp78/BiP	PubMed
	tat	Neurons exposed to HIV-1 Tat induces calcium loss from the endoplasmic reticulum via ryanodine receptor (RyR) and increases the phosphorylated levels of PERK, eIF2a, and XBP1	PubMed

Go to the HIV-1, Human Protein Interaction Database

Interactions

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Products	Interactant	Other Gene	Source	Pubs	Description
Q9NZJ5	Q13217	DNAJC3	HPRD	PubMed
Q9NZJ5	P05198	EIF2S1	HPRD	PubMed
Q9NZJ5	P07900	HSP90AA1	HPRD	PubMed
Q9NZJ5	P11021	HSPA5	HPRD	PubMed
Q9NZJ5	O14920	IKBKB	HPRD	PubMed
Q9NZJ5	Q16236	NFE2L2	HPRD	PubMed
BioGRID:114840	BioGRID:107076	BCL6	BioGRID	PubMed	Affinity Capture-MS
BioGRID:114840	BioGRID:116183	COPS5	BioGRID	PubMed	Affinity Capture-Western
BioGRID:114840	BioGRID:111597	DNAJC3	BioGRID	PubMed	Affinity Capture-Western; Phenotypic Suppression; Reconstituted Complex
BioGRID:114840	BioGRID:108285	EIF2S1	BioGRID	PubMed	Biochemical Activity
BioGRID:114840	BioGRID:109552	HSP90AA1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:114840	BioGRID:113036	HSP90B1	BioGRID	PubMed	Affinity Capture-Western
BioGRID:114840	BioGRID:109541	HSPA5	BioGRID	PubMed	Affinity Capture-Western
BioGRID:114840	BioGRID:110852	NFE2L2	BioGRID	PubMed	Biochemical Activity; Two-hybrid
BioGRID:114840	BioGRID:127820	RHBDL3	BioGRID	PubMed	Affinity Capture-Western

Pathways from BioSystems

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Alzheimer's disease, organism-specific biosystem (from KEGG)
Alzheimer's disease, organism-specific biosystemAlzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-b...
Alzheimer's disease, conserved biosystem (from KEGG)
Alzheimer's disease, conserved biosystemAlzheimer's disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-b...
Alzheimers Disease, organism-specific biosystem (from WikiPathways)
Alzheimers Disease, organism-specific biosystemThis pathway displays current genes, proteolytic events and other processes associated with the progression of Alzheimer's disease. This pathway was adapted from KEGG on 10/7/2011. Note: mitochondria...
Epstein-Barr virus infection, organism-specific biosystem (from KEGG)
Epstein-Barr virus infection, organism-specific biosystemEpstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is associated with oncogenesis. EBV infection to primary human B lymphocytes leads to induction of EBV-specific HLA-restricted cytotoxi...
Epstein-Barr virus infection, conserved biosystem (from KEGG)
Epstein-Barr virus infection, conserved biosystemEpstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is associated with oncogenesis. EBV infection to primary human B lymphocytes leads to induction of EBV-specific HLA-restricted cytotoxi...
Hepatitis C, organism-specific biosystem (from KEGG)
Hepatitis C, organism-specific biosystemHepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the...
Hepatitis C, conserved biosystem (from KEGG)
Hepatitis C, conserved biosystemHepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the...
Herpes simplex infection, organism-specific biosystem (from KEGG)
Herpes simplex infection, organism-specific biosystemHerpes simplex virus (HSV) infections are very common worldwide, with the prevalence of HSV-1 reaching up to 80%-90%. Primary infection with HSV takes place in the mucosa, followed by the establishme...
Herpes simplex infection, conserved biosystem (from KEGG)
Herpes simplex infection, conserved biosystemHerpes simplex virus (HSV) infections are very common worldwide, with the prevalence of HSV-1 reaching up to 80%-90%. Primary infection with HSV takes place in the mucosa, followed by the establishme...
Influenza A, organism-specific biosystem (from KEGG)
Influenza A, organism-specific biosystemInfluenza is a contagious respiratory disease caused by influenza virus infection. Influenza A virus is responsible for both annual seasonal epidemics and periodic worldwide pandemics. Novel strains ...
Influenza A, conserved biosystem (from KEGG)
Influenza A, conserved biosystemInfluenza is a contagious respiratory disease caused by influenza virus infection. Influenza A virus is responsible for both annual seasonal epidemics and periodic worldwide pandemics. Novel strains ...
Measles, organism-specific biosystem (from KEGG)
Measles, organism-specific biosystemMeasles virus (MV) is highly contagious virus that leads infant death worldwide. Humans are the unique natural reservoir for this virus. It causes severe immunosuppression favouring secondary bacteri...
Measles, conserved biosystem (from KEGG)
Measles, conserved biosystemMeasles virus (MV) is highly contagious virus that leads infant death worldwide. Humans are the unique natural reservoir for this virus. It causes severe immunosuppression favouring secondary bacteri...
Metabolism of proteins, organism-specific biosystem (from REACTOME)
Metabolism of proteins, organism-specific biosystemProtein metabolism comprises the pathways of translation, post-translational modification and protein folding.
PERK regulated gene expression, organism-specific biosystem (from REACTOME)
PERK regulated gene expression, organism-specific biosystemPERK is a single-pass transmembrane protein located in the endoplasmic reticulum (ER) membrane such that the N-terminus of PERK is luminal and the C-terminus is cytosolic. PERK is maintained in an in...
Protein processing in endoplasmic reticulum, organism-specific biosystem (from KEGG)
Protein processing in endoplasmic reticulum, organism-specific biosystemThe endoplasmic reticulum (ER) is a subcellular organelle where proteins are folded with the help of lumenal chaperones. Newly synthesized peptides enter the ER via the sec61 pore and are glycosylate...
Protein processing in endoplasmic reticulum, conserved biosystem (from KEGG)
Protein processing in endoplasmic reticulum, conserved biosystemThe endoplasmic reticulum (ER) is a subcellular organelle where proteins are folded with the help of lumenal chaperones. Newly synthesized peptides enter the ER via the sec61 pore and are glycosylate...
Translation Factors, organism-specific biosystem (from WikiPathways)
Translation Factors, organism-specific biosystemProtein synthesis is the ultimate step of gene expression and a key control point for regulation. In particular, it enables cells to rapidly manipulate protein production without new mRNA synthesis, ...
Unfolded Protein Response, organism-specific biosystem (from REACTOME)
Unfolded Protein Response, organism-specific biosystemThe Unfolded Protein Response (UPR) is a regulatory system that protects the Endoplasmic Reticulum (ER) from overload. The UPR is provoked by the accumulation of improperly folded protein in the ER d...

General gene information

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Markers

SHGC-142459 (e-PCR)
- UniSTS:183303

RH104259 (e-PCR)
- UniSTS:98584

D2S1994 (e-PCR)
- UniSTS:65693

RH46266 (e-PCR)
- UniSTS:91845

RH91182 (e-PCR)
- UniSTS:86985

Genotypes

See EIF2AK3 SNP Geneview Report
See EIF2AK3 SNP Genotype Report
See EIF2AK3 SNP Variation Viewer Report

Homology

Homologs of the EIF2AK3 gene: The EIF2AK3 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, and C.elegans.
Map Viewer (Mouse, Rat)
OrthoDB: The Hierarchical Catalog of Eukaryotic Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
ATP binding	IEA Inferred from Electronic Annotation more info
eukaryotic translation initiation factor 2alpha kinase activity	IDA Inferred from Direct Assay more info	PubMed
eukaryotic translation initiation factor 2alpha kinase activity	IMP Inferred from Mutant Phenotype more info	PubMed
identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein kinase activity	TAS Traceable Author Statement more info	PubMed
protein phosphatase binding	IPI Inferred from Physical Interaction more info
protein serine/threonine kinase activity	ISS Inferred from Sequence or Structural Similarity more info
protein serine/threonine kinase activity	TAS Traceable Author Statement more info

Process	Evidence Code	Pubs
ER overload response	IDA Inferred from Direct Assay more info	PubMed
SREBP signaling pathway	IEA Inferred from Electronic Annotation more info
activation of cysteine-type endopeptidase activity involved in apoptotic process	ISS Inferred from Sequence or Structural Similarity more info
activation of signaling protein activity involved in unfolded protein response	TAS Traceable Author Statement more info
bone mineralization	ISS Inferred from Sequence or Structural Similarity more info
calcium-mediated signaling	ISS Inferred from Sequence or Structural Similarity more info
cellular protein metabolic process	TAS Traceable Author Statement more info
chondrocyte development	ISS Inferred from Sequence or Structural Similarity more info
endocrine pancreas development	IMP Inferred from Mutant Phenotype more info	PubMed
endoplasmic reticulum organization	ISS Inferred from Sequence or Structural Similarity more info
endoplasmic reticulum unfolded protein response	IDA Inferred from Direct Assay more info	PubMed
endoplasmic reticulum unfolded protein response	TAS Traceable Author Statement more info	PubMed
fat cell differentiation	IEA Inferred from Electronic Annotation more info
insulin secretion	ISS Inferred from Sequence or Structural Similarity more info
insulin-like growth factor receptor signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
lactation	IEA Inferred from Electronic Annotation more info
negative regulation of myelination	ISS Inferred from Sequence or Structural Similarity more info
negative regulation of translation	TAS Traceable Author Statement more info	PubMed
negative regulation of translational initiation in response to stress	TAS Traceable Author Statement more info	PubMed
ossification	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of protein binding	IEA Inferred from Electronic Annotation more info
positive regulation of signal transduction	IEA Inferred from Electronic Annotation more info
protein autophosphorylation	IDA Inferred from Direct Assay more info	PubMed
protein autophosphorylation	IMP Inferred from Mutant Phenotype more info	PubMed
protein homooligomerization	IMP Inferred from Mutant Phenotype more info	PubMed
protein phosphorylation	ISS Inferred from Sequence or Structural Similarity more info
regulation of fatty acid metabolic process	IEA Inferred from Electronic Annotation more info
response to endoplasmic reticulum stress	IMP Inferred from Mutant Phenotype more info	PubMed
skeletal system development	ISS Inferred from Sequence or Structural Similarity more info
translation	IEA Inferred from Electronic Annotation more info
virus-infected cell apoptotic process	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
cytoplasm	ISS Inferred from Sequence or Structural Similarity more info
endoplasmic reticulum	IC Inferred by Curator more info	PubMed
endoplasmic reticulum	ISS Inferred from Sequence or Structural Similarity more info
endoplasmic reticulum	TAS Traceable Author Statement more info	PubMed
endoplasmic reticulum membrane	ISS Inferred from Sequence or Structural Similarity more info
endoplasmic reticulum membrane	NAS Non-traceable Author Statement more info	PubMed
endoplasmic reticulum membrane	TAS Traceable Author Statement more info
integral to membrane	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: eukaryotic translation initiation factor 2-alpha kinase 3

Names: eukaryotic translation initiation factor 2-alpha kinase 3; hsPEK; pancreatic EIF2-alpha kinase; PRKR-like endoplasmic reticulum kinase; eukaryotic translation initiation factor 2 alpha kinase 3

NP_004827.4

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_016424.1 RefSeqGene

Range

5001..75836

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_004836.5 → NP_004827.4 eukaryotic translation initiation factor 2-alpha kinase 3 precursor

Status: REVIEWED

Source sequence(s)

AC062029, AF193339, AK128659, AK315287, BC126354, DA990609

Consensus CDS

CCDS33241.1

UniProtKB/TrEMBL

B3KY45

UniProtKB/Swiss-Prot

Q9NZJ5

Related

ENSP00000307235, OTTHUMP00000207186, ENST00000303236, OTTHUMT00000338233

Conserved Domains (3) summary

cd09768
Location:104 – 420
Blast Score: 1006

Luminal_EIF2AK3; The Luminal domain, a dimerization domain, of the Serine/Threonine protein kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 3

smart00220
Location:881 – 1073
Blast Score: 376

S_TKc; Serine/Threonine protein kinases, catalytic domain

cl09925
Location:881 – 1074
Blast Score: 348

PKc_like; Protein Kinases, catalytic domain

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 104

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

Reference GRCh37.p10 Primary Assembly

Genomic

NC_000002.11 Reference GRCh37.p10 Primary Assembly

Range

88856259..88927094, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000134.1 Alternate HuRef

Range

87778073..87848926, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate CHM1_1.0

Genomic

NC_018913.1 Alternate CHM1_1.0

Range

88639192..88710021, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	ABBA01018817.1 (22133..26709)	None
genomic	ABBA01018818.1	None
genomic	ABBA01018819.1	None
genomic	ABBA01018820.1	None
genomic	AC062029.7	AAY14777.1
genomic	AC104134.4	AAY24331.1
genomic	AF284604.1	AAF91480.1
genomic	AF284605.1	AAF91480.1
genomic	AF284606.1	AAF91480.1
genomic	AF284607.1	AAF91480.1
genomic	AF284608.1	AAF91480.1
genomic	AF284609.1	AAF91480.1
genomic	AF284610.1	AAF91480.1
genomic	AF284611.1	AAF91480.1
genomic	AF284612.1	AAF91480.1
genomic	AF284613.1	AAF91480.1
genomic	AF284614.1	AAF91480.1
genomic	AF284615.1	AAF91480.1
genomic	AMYH01010629.1 (103776..174605)	None
genomic	CH471215.1	EAW77068.1
		EAW77069.1
mRNA	AF110146.1	AAD19961.1
mRNA	AF193339.1	AAF61199.1
mRNA	AI650734.1	None
mRNA	AK128659.1	BAG54707.1
mRNA	AK308312.1	None
mRNA	AK315287.1	BAG37696.1
mRNA	BC126354.1	AAI26355.1
mRNA	BC126356.1	AAI26357.1
mRNA	BQ014181.1	None
mRNA	CN285475.1	None
mRNA	CR749382.1	CAH18234.1
mRNA	DA990609.1	None
mRNA	DB287944.1	None