Biology:EIF2AK3
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Short description: Human protein and coding gene
 Generic protein structure example |
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.[1][2][3][4]
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.[2]
Clinical significance
Patients with mutations in this gene develop Wolcott-Rallison syndrome.[5]
Interactions
EIF2AK3 has been shown to interact with DNAJC3,[6] NFE2L2,[7] and endoplasmic reticulum chaperone BiP (Hsp70).[8]
Inhibitors
- GSK2606414
- 3-Fluoro-GSK2606414
References
- ↑ "Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control". Molecular and Cellular Biology 18 (12): 7499–7509. December 1998. doi:10.1128/MCB.18.12.7499. PMID 9819435.
- ↑ 2.0 2.1 "Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase". Nature 397 (6716): 271–274. January 1999. doi:10.1038/16729. PMID 9930704. Bibcode: 1999Natur.397..271H.
- ↑ "Assignment of pancreatic eIF-2alpha kinase (EIF2AK3) to human chromosome band 2p12 by radiation hybrid mapping and in situ hybridization". Cytogenetics and Cell Genetics 86 (3–4): 327–328. 1999. doi:10.1159/000015328. PMID 10575235.
- ↑ "Entrez Gene: EIF2AK3 eukaryotic translation initiation factor 2-alpha kinase 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9451.
- ↑ "Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome". Journal of Inherited Metabolic Disease 31 (Suppl 2): S293–S297. December 2008. doi:10.1007/s10545-008-0866-1. PMID 18500571.
- ↑ "Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK". Proceedings of the National Academy of Sciences of the United States of America 99 (25): 15920–15925. December 2002. doi:10.1073/pnas.252341799. PMID 12446838. Bibcode: 2002PNAS...9915920Y.
- ↑ "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology 23 (20): 7198–7209. October 2003. doi:10.1128/MCB.23.20.7198-7209.2003. PMID 14517290.
- ↑ "Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response". Nature Cell Biology 2 (6): 326–332. June 2000. doi:10.1038/35014014. PMID 10854322.
Further reading
- "A synthetic peptide substrate for initiation factor-2 kinases". Biochemical and Biophysical Research Communications 178 (2): 430–437. July 1991. doi:10.1016/0006-291X(91)90125-Q. PMID 1677563.
- "Mammalian eukaryotic initiation factor 2 alpha kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast". Proceedings of the National Academy of Sciences of the United States of America 90 (10): 4616–4620. May 1993. doi:10.1073/pnas.90.10.4616. PMID 8099443. Bibcode: 1993PNAS...90.4616D.
- "Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control". Molecular and Cellular Biology 18 (12): 7499–7509. December 1998. doi:10.1128/MCB.18.12.7499. PMID 9819435.
- "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". The Biochemical Journal 346 (2): 281–293. March 2000. doi:10.1042/0264-6021:3460281. PMID 10677345.
- "EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome". Nature Genetics 25 (4): 406–409. August 2000. doi:10.1038/78085. PMID 10932183.
- "Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation". The Journal of Biological Chemistry 276 (45): 41620–41628. November 2001. doi:10.1074/jbc.M103674200. PMID 11555640.
- "Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress". The Journal of Biological Chemistry 277 (21): 18728–18735. May 2002. doi:10.1074/jbc.M200903200. PMID 11907036.
- "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". The Biochemical Journal 366 (2): 585–594. September 2002. doi:10.1042/BJ20020391. PMID 12014989.
- "Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene". Diabetes 51 (7): 2301–2305. July 2002. doi:10.2337/diabetes.51.7.2301. PMID 12086964.
- "Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha". Molecular and Cellular Biology 22 (21): 7405–7416. November 2002. doi:10.1128/MCB.22.21.7405-7416.2002. PMID 12370288.
- "Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha". Molecular and Cellular Biology 22 (24): 8506–8513. December 2002. doi:10.1128/MCB.22.24.8506-8513.2002. PMID 12446770.
- "Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK". Proceedings of the National Academy of Sciences of the United States of America 99 (25): 15920–15925. December 2002. doi:10.1073/pnas.252341799. PMID 12446838. Bibcode: 2002PNAS...9915920Y.
- "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". Journal of Virology 77 (6): 3578–3585. March 2003. doi:10.1128/JVI.77.6.3578-3585.2003. PMID 12610133.
- "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology 23 (20): 7198–7209. October 2003. doi:10.1128/MCB.23.20.7198-7209.2003. PMID 14517290.
- "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology 22 (6): 707–716. June 2004. doi:10.1038/nbt971. PMID 15146197.
- "Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity". Diabetes 53 (7): 1876–1883. July 2004. doi:10.2337/diabetes.53.7.1876. PMID 15220213.
- "The EIF2AK3 gene region and type I diabetes in subjects from South India". Genes and Immunity 5 (8): 648–652. December 2004. 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.
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