EIF2AK3

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; OMA:EIF2AK3 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) [1] Band 2p11.2 Start 88,556,741 bp [1] End 88,691,518 bp [1]
Gene location (Mouse) Chr. Chromosome 6 (mouse) [2] Band 6|6 C1 Start 70,821,499 bp [2] End 70,882,229 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in body of pancreas mucosa of paranasal sinus Achilles tendon pylorus parotid gland nasal epithelium mucosa of sigmoid colon tibia epithelium of nasopharynx trachea Top expressed in submandibular gland lacrimal gland parotid gland granulocyte seminal vesicula calvaria islet of Langerhans lumbar spinal ganglion epithelium of stomach decidua More reference expression data BioGPS 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 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 protein autophosphorylation positive regulation of vascular endothelial growth factor production positive regulation of transcription by RNA polymerase I 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 – 88.69 Mb Chr 6: 70.82 – 70.88 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]}

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] NFE2L2, ^[11] and endoplasmic reticulum chaperone BiP (Hsp70). ^[12]

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 (December 1998). "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. doi:10.1128/MCB.18.12.7499. PMC   109330 . PMID   9819435.
6. Harding HP, Zhang Y, Ron D (January 1999). "Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase". Nature. 397 (6716): 271–274. Bibcode:1999Natur.397..271H. 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". Cytogenetics and Cell Genetics. 86 (3–4): 327–328. 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 (December 2008). "Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome". Journal of Inherited Metabolic Disease. 31 (Suppl 2): S293 –S297. 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". Proceedings of the National Academy of Sciences of the United States of America. 99 (25): 15920–15925. Bibcode:2002PNAS...9915920Y. 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". Molecular and Cellular Biology. 23 (20): 7198–7209. doi:10.1128/MCB.23.20.7198-7209.2003. PMC   230321 . PMID   14517290.
12. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (June 2000). "Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response". Nature Cell Biology. 2 (6): 326–332. doi:10.1038/35014014. PMID   10854322. S2CID   22684712.

Further reading

• Mellor H, Proud CG (July 1991). "A synthetic peptide substrate for initiation factor-2 kinases". Biochemical and Biophysical Research Communications. 178 (2): 430–437. Bibcode:1991BBRC..178..430M. doi:10.1016/0006-291X(91)90125-Q. PMID   1677563.
• Dever TE, Chen JJ, Barber GN, Cigan AM, Feng L, Donahue TF, et al. (May 1993). "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. Bibcode:1993PNAS...90.4616D. 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 (December 1998). "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. doi:10.1128/MCB.18.12.7499. PMC   109330 . PMID   9819435.
• Sood R, Porter AC, Ma K, Quilliam LA, Wek RC (March 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". The Biochemical Journal. 346 (2): 281–293. doi:10.1042/0264-6021:3460281. PMC   1220852 . PMID   10677345.
• Delépine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (August 2000). "EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome". Nature Genetics. 25 (4): 406–409. doi:10.1038/78085. PMID   10932183. S2CID   24521894.
• Saelens X, Kalai M, Vandenabeele P (November 2001). "Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation". The Journal of Biological Chemistry. 276 (45): 41620–41628. doi: 10.1074/jbc.M103674200 . PMID   11555640.
• Ma K, Vattem KM, Wek RC (May 2002). "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. doi: 10.1074/jbc.M200903200 . PMID   11907036.
• Okada T, Yoshida H, Akazawa R, Negishi M, Mori K (September 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". The Biochemical Journal. 366 (2): 585–594. doi:10.1042/BJ20020391. PMC   1222788 . PMID   12014989.
• Biason-Lauber A, Lang-Muritano M, Vaccaro T, Schoenle EJ (July 2002). "Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene". Diabetes. 51 (7): 2301–2305. doi: 10.2337/diabetes.51.7.2301 . PMID   12086964.
• Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, et al. (November 2002). "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. 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 (December 2002). "Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha". Molecular and Cellular Biology. 22 (24): 8506–8513. 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 (December 2002). "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. Bibcode:2002PNAS...9915920Y. doi: 10.1073/pnas.252341799 . PMC   138540 . PMID   12446838.
• Pavio N, Romano PR, Graczyk TM, Feinstone SM, Taylor DR (March 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". Journal of Virology. 77 (6): 3578–3585. 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 (October 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Molecular and Cellular Biology. 23 (20): 7198–7209. 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, et al. (June 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology. 22 (6): 707–716. doi:10.1038/nbt971. PMID   15146197. S2CID   27764390.
• Senée V, Vattem KM, Delépine M, Rainbow LA, Haton C, Lecoq A, et al. (July 2004). "Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity". Diabetes. 53 (7): 1876–1883. doi: 10.2337/diabetes.53.7.1876 . PMID   15220213.
• Allotey RA, Mohan V, McDermott MF, Deepa R, Premalatha G, Hassan Z, et al. (December 2004). "The EIF2AK3 gene region and type I diabetes in subjects from South India". Genes and Immunity. 5 (8): 648–652. doi:10.1038/sj.gene.6364139. PMID   15483661. S2CID   21566833.

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