Biology:EEF2K
 Generic protein structure example |
Eukaryotic elongation factor-2 kinase (eEF-2 kinase or eEF-2K), also known as calmodulin-dependent protein kinase III (CAMKIII) and calcium/calmodulin-dependent eukaryotic elongation factor 2 kinase,[1] is an enzyme that in humans is encoded by the EEF2K gene.[2][3]
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.[2][4]
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.[5][6] 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.[6]
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.[5]
Clinical significance
The activity of this kinase is increased in many cancers and may be a valid target for anti-cancer treatment.[2][7]
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.[8]
Cancer
eEF-2K expression is often upregulated in cancer cells, including breast and pancreatic cancers and promotes cell proliferation, survival, motility/migration, invasion and tumorigenesis.[9][10]
References
- ↑ "EEF2K Gene (Protein Coding)". Weizmann Institute of Science. https://www.genecards.org/cgi-bin/carddisp.pl?gene=EEF2K. "Aliases for EEF2K Gene
Eukaryotic Elongation Factor 2 Kinase
Calcium/Calmodulin-Dependent Eukaryotic Elongation Factor 2 Kinase
EEF-2 Kinase
EC 2.7.11.20
EEF-2K
Calcium/Calmodulin-Dependent Eukaryotic Elongation Factor-2 Kinase
Calmodulin-Dependent Protein Kinase III" - ↑ 2.0 2.1 2.2 "Entrez Gene: EEF2K eukaryotic elongation factor-2 kinase". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29904.
- ↑ "Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase". Proceedings of the National Academy of Sciences of the United States of America 94 (10): 4884–9. May 1997. doi:10.1073/pnas.94.10.4884. PMID 9144159. Bibcode: 1997PNAS...94.4884R.
- ↑ "Phosphorylation of elongation factor 2: a key mechanism regulating gene expression in vertebrates". The New Biologist 2 (10): 843–50. Oct 1990. PMID 1964087.
- ↑ 5.0 5.1 "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. Mar 2012. doi:10.1021/bi201788e. PMID 22329831.
- ↑ 6.0 6.1 "The molecular mechanism of eukaryotic elongation factor 2 kinase activation". The Journal of Biological Chemistry 289 (34): 23901–16. Aug 2014. doi:10.1074/jbc.m114.577148. PMID 25012662.
- ↑ "The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation". Cell 153 (5): 1064–79. May 2013. doi:10.1016/j.cell.2013.04.055. PMID 23706743.
- ↑ "The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine". Biological Psychiatry 73 (12): 1199–203. Jun 2013. doi:10.1016/j.biopsych.2012.09.006. PMID 23062356.
- ↑ "Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer.". PLOS ONE 7 (7): e41171. Mar 20, 2012. doi:10.1371/journal.pone.0041171. PMID 22911754. Bibcode: 2012PLoSO...741171T.
- ↑ "Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells.". Apoptosis 19 (1): 241–58. Jan 22, 2014. doi:10.1007/s10495-013-0927-2. PMID 24193916.
Further reading
- "Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2". The Journal of Biological Chemistry 262 (36): 17299–303. Dec 1987. doi:10.1016/S0021-9258(18)45377-X. PMID 3693353.
- "Regulation of elongation factor-2 by multisite phosphorylation". European Journal of Biochemistry 213 (2): 689–99. Apr 1993. doi:10.1111/j.1432-1033.1993.tb17809.x. PMID 8386634.
- "Mapping the functional domains of elongation factor-2 kinase". Biochemistry 39 (40): 12216–24. Oct 2000. doi:10.1021/bi0007270. PMID 11015200.
- "Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/calmodulin-independent activity". The Biochemical Journal 353 (Pt 3): 621–6. Feb 2001. doi:10.1042/0264-6021:3530621. PMID 11171059.
- "A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta". The EMBO Journal 20 (16): 4360–9. Aug 2001. doi:10.1093/emboj/20.16.4360. PMID 11500363.
- "Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase". The EMBO Journal 20 (16): 4370–9. Aug 2001. doi:10.1093/emboj/20.16.4370. PMID 11500364.
- "Detection of anti-elongation factor 2 kinase (calmodulin-dependent protein kinase III) antibodies in patients with systemic lupus erythematosus". Biochemical and Biophysical Research Communications 293 (3): 1073–6. May 2002. doi:10.1016/S0006-291X(02)00324-8. PMID 12051769.
- "Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants". Molecular Vision 8: 205–20. Jun 2002. PMID 12107410.
- "Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways". The Biochemical Journal 367 (Pt 2): 525–32. Oct 2002. doi:10.1042/BJ20020916. PMID 12171600.
- "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". The Journal of Biological Chemistry 279 (13): 12220–31. Mar 2004. doi:10.1074/jbc.M309773200. PMID 14709557.
- "A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin". Molecular and Cellular Biology 24 (7): 2986–97. Apr 2004. doi:10.1128/MCB.24.7.2986-2997.2004. PMID 15024086.
- "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry". Analytical Chemistry 76 (10): 2763–72. May 2004. doi:10.1021/ac035352d. PMID 15144186.
- "Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain". The FEBS Journal 272 (16): 4211–20. Aug 2005. doi:10.1111/j.1742-4658.2005.04833.x. PMID 16098202.
- "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. Jan 2006. doi:10.1101/gr.4039406. PMID 16344560.
- "Elongation factor-2 kinase: its role in protein synthesis and autophagy". Autophagy 2 (4): 294–6. 2007. doi:10.4161/auto.2857. PMID 16921268.
- "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology 24 (10): 1285–92. Oct 2006. doi:10.1038/nbt1240. PMID 16964243.
- "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–48. Nov 2006. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
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