EIF2AK3 Gene

Name	eukaryotic translation initiation factor 2-alpha kinase 3
Description	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]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n EIF2AK3 (also known as PERK) is a central endoplasmic reticulum (ER) stress sensor that plays a pivotal role in orchestrating the unfolded protein response (UPR) to maintain proteostasis. Upon accumulation of misfolded proteins in the ER, EIF2AK3 is activated to phosphorylate the eukaryotic translation initiation factor 2α (eIF2α), thereby attenuating global protein synthesis while selectively inducing key stress-response proteins. This phosphorylation event not only diminishes the folding load but also triggers expression of transcription factors (such as CHOP) that, if stress persists, steer the cell toward apoptotic pathways (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In parallel, EIF2AK3-dependent signaling promotes cell survival mechanisms; for example, it phosphorylates and activates Nrf2 to bolster antioxidant defenses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, under conditions of proteotoxic stress—such as in models of polyglutamine aggregation—its activity is essential for the initiation of protective autophagy through eIF2α phosphorylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n EIF2AK3 is also uniquely positioned at mitochondria-associated ER membranes (MAMs), where it facilitates ER–mitochondria communication and propagates reactive oxygen species (ROS) signals that influence the commitment to apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In addition, the translational control exerted by EIF2AK3 contributes to the activation of NF-κB by repressing the synthesis of the inhibitory protein IκBα, thereby linking ER stress to inflammatory signaling cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, during extreme metabolic stresses such as hypoxia, EIF2AK3 activity is essential for the integrated stress response that enables tumor and other cells to adapt and survive."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Collectively, EIF2AK3 functions as an integrative node that balances the cellular outcomes of ER stress—promoting adaptive survival via antioxidant and autophagic responses under moderate stress, while switching to apoptotic programs when the stress is unresolvable.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jonathan H Lin, Han Li, Douglas Yasumura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IRE1 signaling affects cell fate during the unfolded protein response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1146361"}], "href": "https://doi.org/10.1126/science.1146361"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17991856"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17991856"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "T Verfaillie, N Rubio, A D Garg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cdd.2012.74"}], "href": "https://doi.org/10.1038/cdd.2012.74"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22705852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22705852"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Sara B Cullinan, Donna Zhang, Mark Hannink, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.23.20.7198-7209.2003"}], "href": "https://doi.org/10.1128/MCB.23.20.7198-7209.2003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14517290"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14517290"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Y Kouroku, E Fujita, I Tanida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.cdd.4401984"}], "href": "https://doi.org/10.1038/sj.cdd.4401984"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16794605"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16794605"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jing Deng, Phoebe D Lu, Yuhong Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.24.23.10161-10168.2004"}], "href": "https://doi.org/10.1128/MCB.24.23.10161-10168.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15542827"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15542827"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Meixia Bi, Christine Naczki, Marianne Koritzinsky, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.emboj.7600777"}], "href": "https://doi.org/10.1038/sj.emboj.7600777"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16148948"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16148948"}]}]}]}
Synonyms	PEK, PERK
Proteins	E2AK3_HUMAN
NCBI Gene ID	9451
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

EIF2AK3 has 13,049 functional associations with biological entities spanning 9 categories (molecular profile, organism, functional term, phrase or reference, disease, phenotype or trait, chemical, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 136 datasets.

Click the + buttons to view associations for EIF2AK3 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

EIF2AK3 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by EIF2AK3 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of EIF2AK3 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of EIF2AK3 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of EIF2AK3 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of EIF2AK3 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of EIF2AK3 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of EIF2AK3 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving EIF2AK3 protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of EIF2AK3 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of EIF2AK3 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of EIF2AK3 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of EIF2AK3 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of EIF2AK3 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with EIF2AK3 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with EIF2AK3 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with EIF2AK3 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of EIF2AK3 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of EIF2AK3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of EIF2AK3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with EIF2AK3 gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with EIF2AK3 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of EIF2AK3 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing EIF2AK3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing EIF2AK3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with EIF2AK3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with EIF2AK3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of EIF2AK3 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with EIF2AK3 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with EIF2AK3 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with EIF2AK3 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with EIF2AK3 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of EIF2AK3 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by EIF2AK3 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving EIF2AK3 gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving EIF2AK3 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with EIF2AK3 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with EIF2AK3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with EIF2AK3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with EIF2AK3 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with EIF2AK3 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.