EIF2AK3

Eukaryotic translation initiation factor 2-alpha kinase 3

Identifiers

EIF2AK3; DKFZp781H1925; PEK; PERK; WRS

External IDs

OMIM: 604032 MGI: 1341830 HomoloGene: 3557 GeneCards: EIF2AK3 Gene

2.7.11.1

Gene Ontology
Molecular function	• nucleotide binding • protein kinase activity • protein serine/threonine kinase activity • protein serine/threonine kinase activity • eukaryotic translation initiation factor 2alpha kinase activity • eukaryotic translation initiation factor 2alpha kinase activity • protein binding • ATP binding • identical protein binding
Cellular component	• cell • cytoplasm • endoplasmic reticulum • endoplasmic reticulum • endoplasmic reticulum • endoplasmic reticulum membrane • endoplasmic reticulum membrane • endoplasmic reticulum membrane • membrane • integral to membrane
Biological process	• skeletal system development • ossification • chondrocyte development • protein phosphorylation • protein phosphorylation • activation of caspase activity • virus-infected cell apoptosis • ER overload response • response to unfolded protein • 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 • 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-mediated signaling pathway • response to endoplasmic reticulum stress • fat cell differentiation • protein autophosphorylation • 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

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 2:
88.86 – 88.93 Mb

Chr 6:
70.79 – 70.86 Mb

PubMed search

[1]

[2]

Eukaryotic translation initiation factor 2-alpha kinase 3 is an enzyme that in humans is encoded by the EIF2AK3 gene.^[1]^[2]^[3] Patients with mutations in this gene develop Wolcott-Rallison syndrome.^[4]

Interactions

EIF2AK3 has been shown to interact with NFE2L2^[5] and DNAJC3.^[6]

References

^ Shi Y, An J, Liang J, Hayes SE, Sandusky GE, Stramm LE, Yang NN (Mar 1999). "Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin in islet delta cells". J Biol Chem 274 (9): 5723–30. doi:10.1074/jbc.274.9.5723. PMID 10026192.
^ Hayes SE, Conner LJ, Stramm LE, Shi Y (Jan 2000). "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". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9451.
^ Søvik O, Njølstad PR, Jellum E, Molven A (May 2008). "Wolcott-Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome". J. Inherit. Metab. Dis.. doi:10.1007/s10545-008-0866-1. PMID 18500571.
^ Cullinan, Sara B; Zhang Donna, Hannink Mark, Arvisais Edward, Kaufman Randal J, Diehl J Alan (Oct. 2003). "Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival". Mol. Cell. Biol. (United States) 23 (20): 7198–209. doi:10.1128/MCB.23.20.7198-7209.2003. ISSN 0270-7306. PMC 230321. PMID 14517290. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=230321.
^ Yan, Wei; Frank Christopher L, Korth Marcus J, Sopher Bryce L, Novoa Isabel, Ron David, Katze Michael G (Dec. 2002). "Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK". Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (25): 15920–5. doi:10.1073/pnas.252341799. ISSN 0027-8424. PMC 138540. PMID 12446838. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=138540.

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, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=46563.
Shi Y, Vattem KM, Sood R, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=109330.
Sood R, Porter AC, Ma K, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1220852.
Delépine M, Nicolino M, Barrett T, et al. (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, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1222788.
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, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=135664.
Marcu MG, Doyle M, Bertolotti A, et al. (2003). "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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139892.
Yan W, Frank CL, Korth MJ, et al. (2003). "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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=138540.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
Pavio N, Romano PR, Graczyk TM, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=149509.
Cullinan SB, Zhang D, Hannink M, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=230321.
Brandenberger R, Wei H, Zhang S, et al. (2005). "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, et al. (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, et al. (2005). "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.

Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)

Serine/threonine-specific protein kinases (EC 2.7.11.1-EC 2.7.11.20)

Non-specific serine/threonine protein kinases (EC 2.7.11.1)	LATS1, LATS2, MAST1, MAST2, STK38, STK38L, CIT, ROCK1, SGK, SGK2, SGK3, Protein kinase B (AKT1, AKT2, AKT3), Ataxia telangiectasia mutated, Mammalian target of rapamycin, EIF-2 kinases (PKR, HRI, EIF2AK3, EIF2AK4), Wee1 (WEE1)

Pyruvate dehydrogenase kinase (EC 2.7.11.2)	PDK1, PDK2, PDK3

Dephospho-(reductase kinase) kinase (EC 2.7.11.3)	AMP-activated protein kinase α (PRKAA1, PRKAA2) · β (PRKAB1, PRKAB2) · γ (PRKAG1, PRKAG2, PRKAG3)

(3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)) (EC 2.7.11.4)	BCKDK, BCKDHA, BCKDHB

(isocitrate dehydrogenase (NADP+)) kinase (EC 2.7.11.5)	IDH2, IDH3A, IDH3B, IDH3G

(tyrosine 3-monooxygenase) kinase (EC 2.7.11.6)	STK4

Myosin-heavy-chain kinase (EC 2.7.11.7)	Aurora kinase (Aurora A kinase, Aurora B kinase)

Fas-activated serine/threonine kinase (EC 2.7.11.8)	FASTK, STK10

Goodpasture-antigen-binding protein kinase (EC 2.7.11.9)	-

IκB kinase (EC 2.7.11.10)	CHUK, IKK2, TBK1, IKBKE, IKBKG, IKBKAP

cAMP-dependent protein kinase (EC 2.7.11.11)	Protein kinase A, PRKACG, PRKACB, PRKACA, PRKY

cGMP-dependent protein kinase (EC 2.7.11.12)	Protein kinase G, PRKG1

Protein kinase C (EC 2.7.11.13)	Protein kinase C, Protein kinase Cζ, PKC alpha, PRKCB1, PRKCD, PRKCE, PRKCH, PRKCG, PRKCI, PRKCQ, Protein kinase N1, PKN2, PKN3,

Rhodopsin kinase (EC 2.7.11.14)	Rhodopsin kinase

Beta adrenergic receptor kinase (EC 2.7.11.15)	Beta adrenergic receptor kinase, Beta adrenergic receptor kinase-2

G-protein coupled receptor kinases (EC 2.7.11.16)	GRK4, GRK5, GRK6

Ca2+/calmodulin-dependent (EC 2.7.11.17)	BRSK2, CAMK1, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CAMK4, MLCK, CASK, CHEK1, CHEK2, DAPK1, DAPK2, DAPK3, STK11, MAPKAPK2, MAPKAPK3, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MELK, MKNK1, MKNK2, NUAK1, NUAK2, OBSCN, PASK, PHKG1, PHKG2, PIM1, PIM2, PKD1, PRKD2, PRKD3, PSKH1, SNF1LK2, KIAA0999, STK40, SNF1LK, SNRK, SPEG, TSSK2, Kalirin, TRIB1, TRIB2, TRIB3, TRIO, Titin, DCLK1

Myosin light-chain kinase (EC 2.7.11.18)	MYLK, MYLK2, MYLK3, MYLK4

Phosphorylase kinase (EC 2.7.11.19)	PHKA1, PHKA2, PHKB, PHKG1, PHKG2

Elongation factor 2 kinase (EC 2.7.11.20)	EEF2K, STK19

Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)

Polo kinase (EC 2.7.11.21)	PLK1, PLK2, PLK3, PLK4

Cyclin-dependent kinase (EC 2.7.11.22)	CDK1, CDK2, CDKL2, CDK3, CDK4, CDK5, CDKL5, CDK6, CDK7, CDK8, CDK9, CDK10, CDC2L5, CRKRS, PCTK1, PCTK2, PCTK3, PFTK1, CDC2L1

(RNA-polymerase)-subunit kinase (EC 2.7.11.23)	RPS6KA5, RPS6KA4, P70S6 kinase, P70-S6 Kinase 1, RPS6KB2, RPS6KA2, RPS6KA3, RPS6KA1, RPS6KC1

Mitogen-activated protein kinase (EC 2.7.11.24)	Extracellular signal-regulated (MAPK1, MAPK3, MAPK4, MAPK6, MAPK7, MAPK12, MAPK15), C-Jun N-terminal (MAPK8, MAPK9, MAPK10), P38 mitogen-activated protein (MAPK11, MAPK13, MAPK14)

MAP3K (EC 2.7.11.25)	MAP kinase kinase kinases (MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8) RAFs (ARAF, BRAF, KSR1, KSR2), MLKs (MAP3K12, MAP3K13, MAP3K9, MAP3K10, MAP3K11, MAP3K7, ZAK), CDC7, MAP3K14

Tau-protein kinase (EC 2.7.11.26)	TPK1, TTK, GSK-3

(acetyl-CoA carboxylase) kinase (EC 2.7.11.27)	-

Tropomyosin kinase (EC 2.7.11.28)	-

Low-density-lipoprotein receptor kinase (EC 2.7.11.29)	-

Receptor protein serine/threonine kinase (EC 2.7.11.30)	Bone morphogenetic protein receptors (BMPR1, BMPR1A, BMPR1B, BMPR2), ACVR1, ACVR1B, ACVR1C, ACVR2A, ACVR2B, ACVRL1, Anti-Müllerian hormone receptor

Dual-specificity kinases (EC 2.7.12)

MAP2K	MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7

B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6

EIF2AK3

Interactions

References

Further reading