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

Summary

Official Symbol: EIF2AK3provided by HGNC
Official Full Name: eukaryotic translation initiation factor 2 alpha kinase 3provided by HGNC
Primary source: HGNC:HGNC:3255
See related: Ensembl:ENSG00000172071 MIM:604032; AllianceGenome:HGNC:3255
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, leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This protein is thought to modulate mitochondrial function. 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, Sep 2015]
Expression: Ubiquitous expression in thyroid (RPKM 13.4), stomach (RPKM 10.9) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 2p11.2

Exon count:: 21

Annotation release	Status	Assembly	Chr	Location
RS_2023_03	current	GRCh38.p14 (GCF_000001405.40)	2	NC_000002.12 (88556741..88628145, complement)
RS_2023_03	current	T2T-CHM13v2.0 (GCF_009914755.1)	2	NC_060926.1 (88568747..88640715, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (88856259..88926982, 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?

Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation.
Title: Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation.
PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration.
Title: PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration.
Mycobacterium tuberculosis PE_PGRS1 promotes mycobacteria intracellular survival via reducing the concentration of intracellular free Ca[2+] and suppressing endoplasmic reticulum stress.
Title: Mycobacterium tuberculosis PE_PGRS1 promotes mycobacteria intracellular survival via reducing the concentration of intracellular free Ca(2+) and suppressing endoplasmic reticulum stress.
Loss of ATF6alpha in a human carcinoma cell line is compensated not by its paralogue ATF6beta but by sustained activation of the IRE1 and PERK arms for tumor growth in nude mice.
Title: Loss of ATF6α in a human carcinoma cell line is compensated not by its paralogue ATF6β but by sustained activation of the IRE1 and PERK arms for tumor growth in nude mice.
Fatty acid palmitate suppresses FoxO1 expression via PERK and IRE1 unfolded protein response in C2C12 myotubes.
Title: Fatty acid palmitate suppresses FoxO1 expression via PERK and IRE1 unfolded protein response in C2C12 myotubes.
PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells.
Title: PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells.
A non-canonical cGAS-STING-PERK pathway facilitates the translational program critical for senescence and organ fibrosis.
Title: A non-canonical cGAS-STING-PERK pathway facilitates the translational program critical for senescence and organ fibrosis.
PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen.
Title: PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen.
Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation.
Title: Endoplasmic Reticulum Stress in Colonic Mucosa of Ulcerative Colitis Patients Is Mediated by PERK and IRE1 Pathway Activation.
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.

Submit: New GeneRIF Correction See all GeneRIFs (181)

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
Wolcott-Rallison dysplasia MedGen: C0432217 OMIM: 226980 GeneReviews: Not available	Compare labs

EBI GWAS Catalog

Description
Hundreds of variants clustered in genomic loci and biological pathways affect human height. EBI GWAS Catalog EBI GWAS CatalogPubMed
Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. EBI GWAS Catalog EBI GWAS CatalogPubMed
Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci. EBI GWAS Catalog EBI GWAS CatalogPubMed

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 gp160, precursor	env	Knockdown of PERK expression increases intracellular HIV-1 Env expression in human and murine cell lines	PubMed
Tat	tat	HIV-1 Tat induces endoplasmic reticulum (ER) stress response proteins CASP12 (Caspase 12), DDIT3 (CHOP), ROS1, ERN-1 (p-IRE1), EIF2AK3 (p-PERK), and ATF6 in human brain microvascular endothelial cells (HBMECs)	PubMed
	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 Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

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

Homology

Homologs of the EIF2AK3 gene: The EIF2AK3 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, mosquito, and frog.
Orthologs from Annotation Pipeline: 501 organisms have orthologs with human gene EIF2AK3
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables ATP binding	IEA Inferred from Electronic Annotation more info
enables Hsp90 protein binding	IEA Inferred from Electronic Annotation more info
enables enzyme binding	IPI Inferred from Physical Interaction more info	PubMed
enables eukaryotic translation initiation factor 2alpha kinase activity	IDA Inferred from Direct Assay more info	PubMed
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 protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein kinase activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
enables protein phosphatase binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein serine kinase activity	IEA Inferred from Electronic Annotation more info
enables protein serine/threonine kinase activity	ISS Inferred from Sequence or Structural Similarity more info

Process	Evidence Code	Pubs
involved_in ER overload response	IDA Inferred from Direct Assay more info	PubMed
involved_in PERK-mediated unfolded protein response	TAS Traceable Author Statement more info	PubMed
involved_in activation of cysteine-type endopeptidase activity involved in apoptotic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in angiogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in bone mineralization	ISS Inferred from Sequence or Structural Similarity more info
involved_in calcium-mediated signaling	ISS Inferred from Sequence or Structural Similarity more info
involved_in cellular response to amino acid starvation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in cellular response to cold	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in cellular response to glucose starvation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in chondrocyte development	ISS Inferred from Sequence or Structural Similarity more info
involved_in eiF2alpha phosphorylation in response to endoplasmic reticulum stress	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in eiF2alpha phosphorylation in response to endoplasmic reticulum stress	TAS Traceable Author Statement more info	PubMed
involved_in endocrine pancreas development	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in endoplasmic reticulum organization	ISS Inferred from Sequence or Structural Similarity more info
involved_in endoplasmic reticulum unfolded protein response	IDA Inferred from Direct Assay more info	PubMed
involved_in endoplasmic reticulum unfolded protein response	TAS Traceable Author Statement more info	PubMed
involved_in insulin-like growth factor receptor signaling pathway	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of myelination	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of translation	TAS Traceable Author Statement more info	PubMed
involved_in negative regulation of translation in response to stress	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of translational initiation in response to stress	TAS Traceable Author Statement more info	PubMed
involved_in ossification	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in peptidyl-serine phosphorylation	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of gene expression	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of protein localization to nucleus	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of transcription by RNA polymerase I	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of vascular endothelial growth factor production	IMP Inferred from Mutant Phenotype more info	PubMed
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	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of translational initiation by eIF2 alpha phosphorylation	ISS Inferred from Sequence or Structural Similarity more info
involved_in response to endoplasmic reticulum stress	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in response to manganese-induced endoplasmic reticulum stress	IEA Inferred from Electronic Annotation more info
involved_in skeletal system development	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
located_in cytoplasm	ISS Inferred from Sequence or Structural Similarity more info
located_in cytosol	TAS Traceable Author Statement more info
located_in endoplasmic reticulum	IC Inferred by Curator more info	PubMed
located_in endoplasmic reticulum	ISS Inferred from Sequence or Structural Similarity more info
located_in endoplasmic reticulum	TAS Traceable Author Statement more info	PubMed
located_in endoplasmic reticulum membrane	ISS Inferred from Sequence or Structural Similarity more info
located_in endoplasmic reticulum membrane	NAS Non-traceable Author Statement more info	PubMed
located_in endoplasmic reticulum membrane	TAS Traceable Author Statement more info
located_in membrane	HDA more info	PubMed
located_in perinuclear region of cytoplasm	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: PKR-like ER kinase; PRKR-like endoplasmic reticulum kinase; pancreatic EIF2-alpha kinase; pancreatic eIF-2alpha kinase

NP_001300844.1

EC 2.7.11.1

NP_004827.4

EC 2.7.11.1

XP_047302384.1

EC 2.7.11.1

XP_047302385.1

EC 2.7.11.1

XP_047302386.1

EC 2.7.11.1

XP_054200611.1

EC 2.7.11.1

XP_054200612.1

EC 2.7.11.1

XP_054200613.1

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

5113..75836

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_1024

mRNA and Protein(s)

NM_001313915.2 → NP_001300844.1 eukaryotic translation initiation factor 2-alpha kinase 3 isoform 2

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an alternate 5' exon, uses an alternate 5' terminal exon, and initiates translation at a downstream start codon, compared to variant 1. The encoded isoform (2) has a shorter N-terminus compared to isoform 1.

Source sequence(s)

AC062029, AC104134, CB162654, CR749382

UniProtKB/TrEMBL

A0A804HIT4, E7ER02, Q68DI6

Related

ENSP00000507214.1, ENST00000682892.1

Conserved Domains (3) summary

cd09768
Location:1 → 269

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

cd14048
Location:722 → 924

STKc_EIF2AK3_PERK; Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 3 or PKR-like Endoplasmic Reticulum Kinase

cl21453
Location:436 → 512

PKc_like; Protein Kinases, catalytic domain
NM_004836.7 → NP_004827.4 eukaryotic translation initiation factor 2-alpha kinase 3 isoform 1 precursor

See identical proteins and their annotated locations for NP_004827.4

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).

Source sequence(s)

AC062029, AC104134, AK128659, CB162654

Consensus CDS

CCDS33241.1

UniProtKB/Swiss-Prot

Q53SB1, Q9NZJ5

UniProtKB/TrEMBL

B3KY45

Related

ENSP00000307235.3, ENST00000303236.9

Conserved Domains (3) summary

cd09768
Location:104 → 420

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

cd14048
Location:873 → 1075

STKc_EIF2AK3_PERK; Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 3 or PKR-like Endoplasmic Reticulum Kinase

cl21453
Location:587 → 663

PKc_like; Protein Kinases, catalytic domain

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_03

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

88556741..88628145 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_047446428.1 → XP_047302384.1 eukaryotic translation initiation factor 2-alpha kinase 3 isoform X1
XM_047446429.1 → XP_047302385.1 eukaryotic translation initiation factor 2-alpha kinase 3 isoform X2

Related

ENSP00000507355.1, ENST00000684642.1
XM_047446430.1 → XP_047302386.1 eukaryotic translation initiation factor 2-alpha kinase 3 isoform X3

Alternate T2T-CHM13v2.0

Genomic

NC_060926.1 Alternate T2T-CHM13v2.0

Range

88568747..88640715 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054344636.1 → XP_054200611.1 eukaryotic translation initiation factor 2-alpha kinase 3 isoform X1
XM_054344637.1 → XP_054200612.1 eukaryotic translation initiation factor 2-alpha kinase 3 isoform X2
XM_054344638.1 → XP_054200613.1 eukaryotic translation initiation factor 2-alpha kinase 3 isoform X3