EEF2K
| Eukaryotic elongation factor-2 kinase | |||||||||||||
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| Identifiers | |||||||||||||
| Symbols | EEF2K ; HSU93850; eEF-2K | ||||||||||||
| External IDs | OMIM: 606968 MGI: 1195261 HomoloGene: 7299 IUPHAR: 2014 ChEMBL: 5026 GeneCards: EEF2K Gene | ||||||||||||
| EC number | 2.7.11.20 | ||||||||||||
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| RNA expression pattern | |||||||||||||
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| More reference expression data | |||||||||||||
| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 29904 | 13631 | |||||||||||
| Ensembl | ENSG00000103319 | ENSMUSG00000035064 | |||||||||||
| UniProt | O00418 | O08796 | |||||||||||
| RefSeq (mRNA) | NM_013302 | NM_001267710 | |||||||||||
| RefSeq (protein) | NP_037434 | NP_001254639 | |||||||||||
| Location (UCSC) | Chr 16: 22.22 – 22.3 Mb | Chr 7: 120.84 – 120.91 Mb | |||||||||||
| PubMed search | |||||||||||||
Eukaryotic elongation factor-2 kinase (eEF-2 kinase or eEF-2K), also known as calcium/calmodulin-dependent eukaryotic elongation factor 2 kinase (CaMKIII) is an enzyme that in humans is encoded by the EEF2K gene.[1][2]
Function
eEF-2 kinase is a highly conserved protein kinase in the calmodulin-mediated signaling pathway that links multiple up-stream signals to the regulation of protein synthesis. It phosphorylates eukaryotic elongation factor 2 (EEF2) and thus inhibits the EEF2 function.[1][3]
Activation
The activity of eEF-2K is dependent on calcium and calmodulin. Activation of eEF-2K proceeds by a sequential two-step mechanism. First, calcium-calmodulin binds with high affinity to activate the kinase domain, triggering rapid autophosphorylation of Thr-348.[4][5] In the second step, autophosphorylation of Thr-348 leads to a conformational change in the kinase likely supported by the binding of phospho-Thr-348 to an allosteric phosphate binding pocket in the kinase domain. This increases the activity of eEF-2K against its substrate, elongation factor 2.[5]
eEF-2K can gain calcium-independent activity through autophosphorylation of Ser-500. However, calmodulin must remain bound to the enzyme for its activity to be sustained.[4]
Clinical significance
The activity of this kinase is increased in many cancers and may be a valid target for anti-cancer treatment.[1][6]
It is also suggested that eEF-2K may play a role the rapid anti-depressant effects of ketamine through its regulation of neuronal protein synthesis.[7]
References
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Further reading
- Nairn AC, Palfrey HC (1988). "Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2". J. Biol. Chem. 262 (36): 17299–303. PMID 3693353.
- Redpath NT, Price NT, Severinov KV, Proud CG (1993). "Regulation of elongation factor-2 by multisite phosphorylation". Eur. J. Biochem. 213 (2): 689–99. doi:10.1111/j.1432-1033.1993.tb17809.x. PMID 8386634.
- Pavur KS, Petrov AN, Ryazanov AG (2000). "Mapping the functional domains of elongation factor-2 kinase". Biochemistry 39 (40): 12216–24. doi:10.1021/bi0007270. PMID 11015200.
- Diggle TA, Subkhankulova T, Lilley KS, Shikotra N, Willis AE, Redpath NT (2001). "Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/calmodulin-independent activity". Biochem. J. 353 (Pt 3): 621–6. doi:10.1042/0264-6021:3530621. PMC 1221608. PMID 11171059.
- Knebel A, Morrice N, Cohen P (2001). "A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38δ". EMBO J. 20 (16): 4360–9. doi:10.1093/emboj/20.16.4360. PMC 125581. PMID 11500363.
- Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG (2001). "Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase". EMBO J. 20 (16): 4370–9. doi:10.1093/emboj/20.16.4370. PMC 125559. PMID 11500364.
- Arora S, Yang JM, Craft J, Hait W (2002). "Detection of anti-elongation factor 2 kinase (calmodulin-dependent protein kinase III) antibodies in patients with systemic lupus erythematosus". Biochem. Biophys. Res. Commun. 293 (3): 1073–6. doi:10.1016/S0006-291X(02)00324-8. PMID 12051769.
- Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K (2002). "Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants". Mol. Vis. 8: 205–20. PMID 12107410.
- Knebel A, Haydon CE, Morrice N, Cohen P (2002). "Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways". Biochem. J. 367 (Pt 2): 525–32. doi:10.1042/BJ20020916. PMC 1222910. PMID 12171600.
- Browne GJ, Finn SG, Proud CG (2004). "Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398". J. Biol. Chem. 279 (13): 12220–31. doi:10.1074/jbc.M309773200. PMID 14709557.
- Browne GJ, Proud CG (2004). "A Novel mTOR-Regulated Phosphorylation Site in Elongation Factor 2 Kinase Modulates the Activity of the Kinase and Its Binding to Calmodulin". Mol. Cell. Biol. 24 (7): 2986–97. doi:10.1128/MCB.24.7.2986-2997.2004. PMC 371112. PMID 15024086.
- Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC (2004). "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry". Anal. Chem. 76 (10): 2763–72. doi:10.1021/ac035352d. PMID 15144186.
- Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ (2005). "Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain". FEBS J. 272 (16): 4211–20. doi:10.1111/j.1742-4658.2005.04833.x. PMID 16098202.
- Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (2006). "Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
- Hait WN, Wu H, Jin S, Yang JM (2007). "Elongation factor-2 kinase: its role in protein synthesis and autophagy". Autophagy 2 (4): 294–6. doi:10.4161/auto.2857. PMID 16921268.
- Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nat. Biotechnol. 24 (10): 1285–92. doi:10.1038/nbt1240. PMID 16964243.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
- ↑ 1.0 1.1 1.2 "Entrez Gene: EEF2K eukaryotic elongation factor-2 kinase".
- ↑ Ryazanov AG, Ward MD, Mendola CE, Pavur KS, Dorovkov MV, Wiedmann M, Erdjument-Bromage H, Tempst P, Parmer TG, Prostko CR, Germino FJ, Hait WN (May 1997). "Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase". Proc. Natl. Acad. Sci. U.S.A. 94 (10): 4884–9. doi:10.1073/pnas.94.10.4884. PMC 24600. PMID 9144159.
- ↑ Ryazanov AG, Spirin AS (Oct 1990). "Phosphorylation of elongation factor 2: a key mechanism regulating gene expression in vertebrates.". The New biologist 2 (10): 843–50. PMID 1964087.
- ↑ 4.0 4.1 Tavares CD, O'Brien JP, Abramczyk O, Devkota AK, Shores KS, Ferguson SB, Kaoud TS, Warthaka M, Marshall KD, Keller KM, Zhang Y, Brodbelt JS, Ozpolat B, Dalby KN (Mar 20, 2012). "Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence.". Biochemistry 51 (11): 2232–45. doi:10.1021/bi201788e. PMID 22329831.
- ↑ 5.0 5.1 Tavares CD, Ferguson SB, Giles DH, Wang Q, Wellmann RM, O'Brien JP, Warthaka M, Brodbelt JS, Ren P, Dalby KN (Aug 22, 2014). "The molecular mechanism of eukaryotic elongation factor 2 kinase activation.". The Journal of biological chemistry 289 (34): 23901–16. doi:10.1074/jbc.m114.577148. PMID 25012662.
- ↑ Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo AR, Kool M, Agnihotri S, El-Naggar A, Yu B, Somasekharan SP, Faubert B, Bridon G, Tognon CE, Mathers J, Thomas R, Li A, Barokas A, Kwok B, Bowden M, Smith S, Wu X, Korshunov A, Hielscher T, Northcott PA, Galpin JD, Ahern CA, Wang Y, McCabe MG, Collins VP, Jones RG, Pollak M, Delattre O, Gleave ME, Jan E, Pfister SM, Proud CG, Derry WB, Taylor MD, Sorensen PH (May 2013). "The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation". Cell 153 (5): 1064–79. doi:10.1016/j.cell.2013.04.055. PMID 23706743.
- ↑ Monteggia LM, Gideons E, Kavalali ET (Jun 15, 2013). "The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine.". Biological psychiatry 73 (12): 1199–203. doi:10.1016/j.biopsych.2012.09.006. PMID 23062356.