EIF2AK3

Eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is an enzyme that in humans is encoded by the EIF2AK3 gene.[5][6][7][8]

EIF2AK3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4G31, 4G34, 4M7I, 4X7H, 4X7J, 4X7K, 4X7L, 4X7N, 4X7O, 4YZS
Identifiers
Aliases	EIF2AK3, PEK, PERK, WRS, eukaryotic translation initiation factor 2 alpha kinase 3
External IDs	OMIM: 604032 MGI: 1341830 HomoloGene: 3557 GeneCards: EIF2AK3
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p11.2 Start 88,556,741 bp[1] End 88,627,464 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6|6 C1 Start 70,844,515 bp[2] End 70,905,245 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transferase activity • protein kinase activity • Hsp90 protein binding • nucleotide binding • protein homodimerization activity • kinase activity • protein serine/threonine kinase activity • GO:0001948 protein binding • identical protein binding • enzyme binding • protein phosphatase binding • ATP binding • eukaryotic translation initiation factor 2alpha kinase activity Cellular component • cytoplasm • integral component of membrane • endoplasmic reticulum membrane • membrane • integral component of endoplasmic reticulum membrane • endoplasmic reticulum • perinuclear region of cytoplasm • cytosolic ribosome Biological process • skeletal system development • bone mineralization • insulin-like growth factor receptor signaling pathway • negative regulation of translation • regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation • cellular response to glucose starvation • negative regulation of translation in response to stress • ossification • negative regulation of translational initiation in response to stress • phosphorylation • cellular response to amino acid starvation • chondrocyte development • regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway • insulin secretion • endoplasmic reticulum organization • response to endoplasmic reticulum stress • PERK-mediated unfolded protein response • ER overload response • response to manganese-induced endoplasmic reticulum stress • endoplasmic reticulum unfolded protein response • protein phosphorylation • response to unfolded protein • positive regulation of gene expression • cellular response to cold • peptidyl-serine phosphorylation • angiogenesis • eiF2alpha phosphorylation in response to endoplasmic reticulum stress • autophosphorylation • positive regulation of vascular endothelial growth factor production • positive regulation of transcription from RNA polymerase I promoter • protein homooligomerization • activation of cysteine-type endopeptidase activity involved in apoptotic process • negative regulation of myelination • regulation of translation • calcium-mediated signaling • endocrine pancreas development • positive regulation of protein localization to nucleus • regulation of translational initiation by eIF2 alpha phosphorylation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	9451	13666
Ensembl	ENSG00000172071	ENSMUSG00000031668
UniProt	Q9NZJ5	Q9Z2B5
RefSeq (mRNA)	NM_001313915 NM_004836	NM_010121 NM_001313918
RefSeq (protein)	NP_001300844 NP_004827	NP_001300847 NP_034251
Location (UCSC)	Chr 2: 88.56 – 88.63 Mb	Chr 6: 70.84 – 70.91 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

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.[6]

Clinical significance

Patients with mutations in this gene develop Wolcott-Rallison syndrome.[9]

Interactions

EIF2AK3 has been shown to interact with DNAJC3[10] and NFE2L2.[11]

Inhibitors

• GSK2606414
• 3-Fluoro-GSK2606414

References

1. GRCh38: Ensembl release 89: ENSG00000172071 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000031668 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC (Dec 1998). "Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control". Mol. Cell. Biol. 18 (12): 7499–509. doi:10.1128/MCB.18.12.7499. PMC 109330. PMID 9819435.
6. Harding HP, Zhang Y, Ron D (Jan 21, 1999). "Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase". Nature. 397 (6716): 271–4. doi:10.1038/16729. PMID 9930704. S2CID 4416662.
7. Hayes SE, Conner LJ, Stramm LE, Shi Y (1999). "Assignment of pancreatic eIF-2alpha kinase (EIF2AK3) to human chromosome band 2p12 by radiation hybrid mapping and in situ hybridization". Cytogenet. Cell Genet. 86 (3–4): 327–8. doi:10.1159/000015328. PMID 10575235. S2CID 84483593.
8. "Entrez Gene: EIF2AK3 eukaryotic translation initiation factor 2-alpha kinase 3".
9. Søvik O, Njølstad PR, Jellum E, Molven A (May 2008). "Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome". J. Inherit. Metab. Dis. 31 Suppl 2: S293–7. doi:10.1007/s10545-008-0866-1. PMID 18500571. S2CID 1751676.
10. Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, Katze MG (December 2002). "Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK". Proc. Natl. Acad. Sci. U.S.A. 99 (25): 15920–5. doi:10.1073/pnas.252341799. PMC 138540. PMID 12446838.
11. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (October 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Mol. Cell. Biol. 23 (20): 7198–209. doi:10.1128/MCB.23.20.7198-7209.2003. PMC 230321. PMID 14517290.

Further reading

• Mellor H, Proud CG (1991). "A synthetic peptide substrate for initiation factor-2 kinases". Biochem. Biophys. Res. Commun. 178 (2): 430–7. doi:10.1016/0006-291X(91)90125-Q. PMID 1677563.
• Dever TE, Chen JJ, Barber GN, Cigan AM, Feng L, Donahue TF, London IM, Katze MG, Hinnebusch AG (1993). "Mammalian eukaryotic initiation factor 2 alpha kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast". Proc. Natl. Acad. Sci. U.S.A. 90 (10): 4616–20. doi:10.1073/pnas.90.10.4616. PMC 46563. PMID 8099443.
• Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC (1998). "Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control". Mol. Cell. Biol. 18 (12): 7499–509. doi:10.1128/MCB.18.12.7499. PMC 109330. PMID 9819435.
• Sood R, Porter AC, Ma K, Quilliam LA, Wek RC (2000). "Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress". Biochem. J. 346 (2): 281–93. doi:10.1042/0264-6021:3460281. PMC 1220852. PMID 10677345.
• Delépine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000). "EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome". Nat. Genet. 25 (4): 406–9. doi:10.1038/78085. PMID 10932183. S2CID 24521894.
• Saelens X, Kalai M, Vandenabeele P (2001). "Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation". J. Biol. Chem. 276 (45): 41620–8. doi:10.1074/jbc.M103674200. PMID 11555640.
• Ma K, Vattem KM, Wek RC (2002). "Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress". J. Biol. Chem. 277 (21): 18728–35. doi:10.1074/jbc.M200903200. PMID 11907036.
• Okada T, Yoshida H, Akazawa R, Negishi M, Mori K (2002). "Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response". Biochem. J. 366 (Pt 2): 585–94. doi:10.1042/BJ20020391. PMC 1222788. PMID 12014989.
• Biason-Lauber A, Lang-Muritano M, Vaccaro T, Schoenle EJ (2002). "Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene". Diabetes. 51 (7): 2301–5. doi:10.2337/diabetes.51.7.2301. PMID 12086964.
• Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, Koromilas A, Wouters BG (2002). "Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha". Mol. Cell. Biol. 22 (21): 7405–16. doi:10.1128/MCB.22.21.7405-7416.2002. PMC 135664. PMID 12370288.
• Marcu MG, Doyle M, Bertolotti A, Ron D, Hendershot L, Neckers L (2002). "Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha". Mol. Cell. Biol. 22 (24): 8506–13. doi:10.1128/MCB.22.24.8506-8513.2002. PMC 139892. PMID 12446770.
• Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, Katze MG (2002). "Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK". Proc. Natl. Acad. Sci. U.S.A. 99 (25): 15920–5. doi:10.1073/pnas.252341799. PMC 138540. PMID 12446838.
• Pavio N, Romano PR, Graczyk TM, Feinstone SM, Taylor DR (2003). "Protein synthesis and endoplasmic reticulum stress can be modulated by the hepatitis C virus envelope protein E2 through the eukaryotic initiation factor 2alpha kinase PERK". J. Virol. 77 (6): 3578–85. doi:10.1128/JVI.77.6.3578-3585.2003. PMC 149509. PMID 12610133.
• Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Mol. Cell. Biol. 23 (20): 7198–209. doi:10.1128/MCB.23.20.7198-7209.2003. PMC 230321. PMID 14517290.
• Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW (2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nat. Biotechnol. 22 (6): 707–16. doi:10.1038/nbt971. PMID 15146197. S2CID 27764390.
• Senée V, Vattem KM, Delépine M, Rainbow LA, Haton C, Lecoq A, Shaw NJ, Robert JJ, Rooman R, Diatloff-Zito C, Michaud JL, Bin-Abbas B, Taha D, Zabel B, Franceschini P, Topaloglu AK, Lathrop GM, Barrett TG, Nicolino M, Wek RC, Julier C (2004). "Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity". Diabetes. 53 (7): 1876–83. doi:10.2337/diabetes.53.7.1876. PMID 15220213.
• Allotey RA, Mohan V, McDermott MF, Deepa R, Premalatha G, Hassan Z, Cassell PG, North BV, Vaxillaire M, Mein CA, Swan DC, O'Grady E, Ramachandran A, Snehalatha C, Sinnot PJ, Hemmatpour SK, Froguel P, Hitman GA (2004). "The EIF2AK3 gene region and type I diabetes in subjects from South India". Genes Immun. 5 (8): 648–52. doi:10.1038/sj.gene.6364139. PMID 15483661.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.