EIF2AK3
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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.[4][5][6][7]
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.[5]
Clinical significance
Patients with mutations in this gene develop Wolcott-Rallison syndrome.[8]
Interactions
EIF2AK3 has been shown to interact with DNAJC3[9] and NFE2L2.[10]
Inhibitors
- GSK2606414
- 3-Fluoro-GSK2606414
References
- ↑ "Diseases that are genetically associated with EIF2AK3 view/edit references on wikidata".
- ↑ "Human PubMed Reference:".
- ↑ "Mouse PubMed Reference:".
- ↑ 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. - 1 2 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.
- ↑ 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.
- ↑ "Entrez Gene: EIF2AK3 eukaryotic translation initiation factor 2-alpha kinase 3".
- ↑ 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.
- ↑ 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.
- ↑ 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.
- 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.
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