EIF2AK4 eukaryotic translation initiation factor 2 alpha kinase 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: EIF2AK4provided by HGNC
Official Full Name: eukaryotic translation initiation factor 2 alpha kinase 4provided by HGNC
Primary source: HGNC:HGNC:19687
See related: Ensembl:ENSG00000128829 MIM:609280; AllianceGenome:HGNC:19687
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: GCN2; PVOD2
Summary: This gene encodes a member of a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2), resulting in the downregulaton of protein synthesis. The encoded protein responds to amino acid deprivation by binding uncharged transfer RNAs. It may also be activated by glucose deprivation and viral infection. Mutations in this gene have been found in individuals suffering from autosomal recessive pulmonary venoocclusive-disease-2. [provided by RefSeq, Mar 2014]
Expression: Ubiquitous expression in prostate (RPKM 9.5), thyroid (RPKM 9.2) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 15q15.1

Exon count:: 39

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	15	NC_000015.10 (39934115..40035591)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	15	NC_060939.1 (37739435..37840931)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	15	NC_000015.9 (40226316..40327792)

Chromosome 15 - NC_000015.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues 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?

GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.
Title: GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.
The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.
Title: The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.
Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension.
Title: Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension.
Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions.
Title: Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions.
Downregulation of nutrition sensor GCN2 in macrophages contributes to poor wound healing in diabetes.
Title: Downregulation of nutrition sensor GCN2 in macrophages contributes to poor wound healing in diabetes.
Hepatitis E Virus Protease Inhibits the Activity of Eukaryotic Initiation Factor 2-Alpha Kinase 4 and Promotes Virus Survival.
Title: Hepatitis E Virus Protease Inhibits the Activity of Eukaryotic Initiation Factor 2-Alpha Kinase 4 and Promotes Virus Survival.
Contributions of Ccr4 and Gcn2 to the Translational Response of C. neoformans to Host-Relevant Stressors and Integrated Stress Response Induction.
Title: Contributions of Ccr4 and Gcn2 to the Translational Response of C. neoformans to Host-Relevant Stressors and Integrated Stress Response Induction.
A new mutation in the EIF2AK4 gene in familial pulmonary veno-occlusive disease.
Title: A new mutation in the EIF2AK4 gene in familial pulmonary veno-occlusive disease.
Multiple Roles of the Stress Sensor GCN2 in Immune Cells.
Title: Multiple Roles of the Stress Sensor GCN2 in Immune Cells.
Disruption of GCN2 Pathway Aggravates Vascular and Parenchymal Remodeling during Pulmonary Fibrosis.
Title: Disruption of GCN2 Pathway Aggravates Vascular and Parenchymal Remodeling during Pulmonary Fibrosis.

Submit: New GeneRIF Correction See all GeneRIFs (77)

Phenotypes

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Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Familial pulmonary capillary hemangiomatosis MedGen: C0340848 OMIM: 234810 GeneReviews: Not available	Compare labs

EBI GWAS Catalog

Description
Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genetic variants near PDGFRA are associated with corneal curvature in Australians. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome wide association study: searching for genes underlying body mass index in the Chinese. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study supports the role of the immunological system and of the neurodevelopmental processes in response to haloperidol treatment. 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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Replication interactions

Interaction	Pubs
Knockdown of GCN2 by siRNA enhances HIV-1 infectivity in HeLa P4 cells	PubMed

Protein interactions

Protein	Gene	Interaction	Pubs
integrase	gag-pol	HIV-1 IN binds GCN2 through its residues 350-500. IN restores protein synthesis following a stress induced by amino acid starvation, which results in GCN2 activation	PubMed
retropepsin	gag-pol	HIV-1 PR directly cleaves GCN2 at amino acid residues 560-561, which leads to inactivate GCN2 activity	PubMed
	gag-pol	Viral RNA produced during HIV-1 infection activates GCN2 leading to inhibition of viral RNA translation, and that HIV-1 PR cleaves GCN2 to overcome its antiviral effect	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

RH17797 (e-PCR)
- UniSTS:34104

D8S554 (e-PCR), detects polymorphism
- UniSTS:31564

STS-N75547 (e-PCR)
- UniSTS:26733

A004I33 (e-PCR)
- UniSTS:43762

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables 3-phosphoinositide-dependent protein kinase activity	IEA Inferred from Electronic Annotation more info
enables AMP-activated protein kinase activity	IEA Inferred from Electronic Annotation more info
enables ATP binding	IEA Inferred from Electronic Annotation more info
enables DNA-dependent protein kinase activity	IEA Inferred from Electronic Annotation more info
enables Rho-dependent protein serine/threonine kinase activity	IEA Inferred from Electronic Annotation more info
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	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 eukaryotic translation initiation factor 2alpha kinase activity	ISS Inferred from Sequence or Structural Similarity more info	PubMed
enables histone H2AS1 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H2AS121 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H2AT120 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H2AXS139 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H2BS14 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H2BS36 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H3S10 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H3S28 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H3S57 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H3T11 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H3T3 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H3T45 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H3T6 kinase activity	IEA Inferred from Electronic Annotation more info
enables histone H4S1 kinase activity	IEA Inferred from Electronic Annotation more info
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
enables ribosomal protein S6 kinase activity	IEA Inferred from Electronic Annotation more info
enables tRNA binding	ISS Inferred from Sequence or Structural Similarity more info

Process	Evidence Code	Pubs
involved_in DNA damage checkpoint signaling	IEA Inferred from Electronic Annotation more info
involved_in GCN2-mediated signaling	IDA Inferred from Direct Assay more info	PubMed
involved_in GCN2-mediated signaling	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in GCN2-mediated signaling	ISS Inferred from Sequence or Structural Similarity more info
involved_in T cell activation involved in immune response	ISS Inferred from Sequence or Structural Similarity more info
involved_in adaptive immune response	IEA Inferred from Electronic Annotation more info
involved_in cellular response to UV	ISS Inferred from Sequence or Structural Similarity more info
involved_in cellular response to amino acid starvation	IBA Inferred from Biological aspect of Ancestor 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 chromatin remodeling	IEA Inferred from Electronic Annotation more info
involved_in defense response to virus	IEA Inferred from Electronic Annotation more info
involved_in eiF2alpha phosphorylation in response to endoplasmic reticulum stress	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in learning	ISS Inferred from Sequence or Structural Similarity more info
involved_in long-term memory	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation by host of viral genome replication	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of CREB transcription factor activity	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of neuron differentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of translational initiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of translational initiation in response to stress	IBA Inferred from Biological aspect of Ancestor more info
involved_in negative regulation of translational initiation in response to stress	ISS Inferred from Sequence or Structural Similarity more info
involved_in neuron projection extension	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of adaptive immune response	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of defense response to virus by host	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of long-term synaptic potentiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of translational initiation in response to starvation	ISS Inferred from Sequence or Structural Similarity more info
involved_in protein autophosphorylation	ISS Inferred from Sequence or Structural Similarity more info
involved_in protein phosphorylation	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of feeding behavior	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of translational initiation	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of translational initiation by eIF2 alpha phosphorylation	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 viral translation	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
is_active_in cytoplasm	IBA Inferred from Biological aspect of Ancestor more info
located_in cytoplasm	ISS Inferred from Sequence or Structural Similarity more info
is_active_in cytosol	IBA Inferred from Biological aspect of Ancestor more info
located_in cytosolic ribosome	ISS Inferred from Sequence or Structural Similarity more info
is_active_in nucleus	IBA Inferred from Biological aspect of Ancestor more info

General protein information

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Preferred Names: eIF-2-alpha kinase GCN2

Names: GCN2 eIF2alpha kinase; GCN2-like protein; general control nonderepressible 2

NP_001013725.2

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_034053.1 RefSeqGene

Range

4992..106468

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001013703.4 → NP_001013725.2 eIF-2-alpha kinase GCN2

See identical proteins and their annotated locations for NP_001013725.2

Status: REVIEWED

Source sequence(s)

AB037759, AC012377, AL157497, BC009350, BC014915, BC078179, CN286138

Consensus CDS

CCDS42016.1

UniProtKB/Swiss-Prot

C9JEC4, Q69YL7, Q6DC97, Q96GN6, Q9H5K1, Q9NSQ3, Q9NSZ5, Q9P2K8, Q9UJ56

UniProtKB/TrEMBL

H0YME5

Related

ENSP00000263791.5, ENST00000263791.10

Conserved Domains (8) summary

smart00220
Location:590 → 1001

S_TKc; Serine/Threonine protein kinases, catalytic domain

COG0124
Location:1065 → 1490

HisS; Histidyl-tRNA synthetase [Translation, ribosomal structure and biogenesis]

cd14012
Location:299 → 538

PK_eIF2AK_GCN2_rpt1; Pseudokinase domain, repeat 1, of eukaryotic translation Initiation Factor 2-Alpha Kinase 4 or General Control Non-derepressible-2

cd14046
Location:583 → 999

STKc_EIF2AK4_GCN2_rpt2; Catalytic domain, repeat 2, of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 4 or General Control Non-derepressible-2

pfam00069
Location:296 → 539

Pkinase; Protein kinase domain

pfam05773
Location:18 → 134

RWD; RWD domain

cl00266
Location:1395 → 1641

HGTP_anticodon; HGTP anticodon binding domain, as found at the C-terminus of histidyl, glycyl, threonyl and prolyl tRNA synthetases, which are classified as a group of class II aminoacyl-tRNA synthetases (aaRS). In aaRSs, the anticodon binding domain is responsible for ...

cl00268
Location:1061 → 1385

class_II_aaRS-like_core; Class II tRNA amino-acyl synthetase-like catalytic core domain. Class II amino acyl-tRNA synthetases (aaRS) share a common fold and generally attach an amino acid to the 3' OH of ribose of the appropriate tRNA. PheRS is an exception in that it attaches ...