EIF2AK3

Eukaryotic translation initiation factor 2-alpha kinase 3
Structure of the kinase domain of PERK bound to an inhibitor (yellow) from PDB entry 4g31[1]
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4G31​, 4G34​
Identifiers
Symbols	EIF2AK3 ; PEK; PERK; WRS
External IDs	OMIM: 604032 MGI: 1341830 HomoloGene: 3557 IUPHAR: 2017 ChEMBL: 6030 GeneCards: EIF2AK3 Gene
EC number	2.7.11.1
Gene ontology Molecular function • protein kinase activity • protein serine/threonine kinase activity • eukaryotic translation initiation factor 2alpha kinase activity • protein binding • ATP binding • protein phosphatase binding • identical protein binding Cellular component • cytoplasm • endoplasmic reticulum • endoplasmic reticulum membrane • integral to membrane Biological process • skeletal system development • ossification • chondrocyte development • translation • protein phosphorylation • activation of cysteine-type endopeptidase activity involved in apoptotic process • virus-infected cell apoptotic process • ER overload response • activation of signaling protein activity involved in unfolded protein response • endoplasmic reticulum organization • lactation • positive regulation of signal transduction • negative regulation of translation • regulation of fatty acid metabolic process • calcium-mediated signaling • insulin secretion • bone mineralization • endoplasmic reticulum unfolded protein response • endocrine pancreas development • negative regulation of myelination • negative regulation of translational initiation in response to stress • positive regulation of protein binding • SREBP signaling pathway • response to endoplasmic reticulum stress • cellular protein metabolic process • fat cell differentiation • protein autophosphorylation • insulin-like growth factor receptor signaling pathway • protein homooligomerization Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	9451	13666
Ensembl	ENSG00000172071	ENSMUSG00000031668
UniProt	Q9NZJ5	Q9Z2B5
RefSeq (mRNA)	NM_004836	NM_010121
RefSeq (protein)	NP_004827	NP_034251
Location (UCSC)	Chr 2: 88.86 – 88.93 Mb	Chr 6: 70.84 – 70.91 Mb
PubMed search

Eukaryotic translation initiation factor 2-alpha kinase 3, also known as PKR-like endoplasmic reticulum kinase or protein kinase R (PKR)-like endoplasmic reticulum kinase, is an enzyme that in humans is encoded by the EIF2AK3 gene.^[2][3][4][5]

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.^[3]

Clinical significance

Patients with mutations in this gene develop Wolcott-Rallison syndrome.^[6]

Interactions

EIF2AK3 has been shown to interact with DNAJC3^[7] and NFE2L2.^[8]

Inhibitors

• GSK2606414
• 3-Fluoro-GSK2606414

References

1. "Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK).". J.Med.Chem 55 (16): 7193–207. 2012. doi:10.1021/jm300713s. PMID 22827572.
2. 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.
3. 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.
4. 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.
5. "Entrez Gene: EIF2AK3 eukaryotic translation initiation factor 2-alpha kinase 3".
6. 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.
7. 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.
8. 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. 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 Pt 2 (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.
• 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.
• 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.