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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''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''',<ref name="GeneCards">{{cite web|title=EEF2K Gene (Protein Coding)|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=EEF2K|website=GeneCards|publisher=Weizmann Institute of Science|accessdate=4 November 2015|quote=Aliases for EEF2K Gene<br />Eukaryotic Elongation Factor 2 Kinase<br />Calcium/Calmodulin-Dependent Eukaryotic Elongation Factor 2 Kinase<br />EEF-2 Kinase<br />EC 2.7.11.20<br />EEF-2K<br />Calcium/Calmodulin-Dependent Eukaryotic Elongation Factor-2 Kinase<br />Calmodulin-Dependent Protein Kinase III}}</ref> is an [[enzyme]] that in humans is encoded by the ''EEF2K'' [[gene]].<ref name="entrez"/><ref name="pmid9144159">{{cite journal | vauthors = 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 | title = Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 10 | pages = 4884–9 | date = May 1997 | pmid = 9144159 | pmc = 24600 | doi = 10.1073/pnas.94.10.4884 }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Eukaryotic elongation factor-2 kinase
| HGNCid = 24615
| Symbol = EEF2K
| AltSymbols =; HSU93850; MGC45041; eEF-2K
| OMIM = 606968
| ECnumber = 
| Homologene = 7299
| MGIid = 1195261
| GeneAtlas_image1 = PBB_GE_EEF2K_gnf1h00131_at_tn.png
| GeneAtlas_image2 = PBB_GE_EEF2K_gnf1h00132_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0004674 |text = protein serine/threonine kinase activity}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}} {{GNF_GO|id=GO:0005516 |text = calmodulin binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0008135 |text = translation factor activity, nucleic acid binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0006414 |text = translational elongation}} {{GNF_GO|id=GO:0006468 |text = protein amino acid phosphorylation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 29904
    | Hs_Ensembl = ENSG00000103319
    | Hs_RefseqProtein = NP_037434
    | Hs_RefseqmRNA = NM_013302
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 16
    | Hs_GenLoc_start = 22125248
    | Hs_GenLoc_end = 22205450
    | Hs_Uniprot = O00418
    | Mm_EntrezGene = 13631
    | Mm_Ensembl = ENSMUSG00000035064
    | Mm_RefseqmRNA = NM_007908
    | Mm_RefseqProtein = NP_031934
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 7
    | Mm_GenLoc_start = 120634004
    | Mm_GenLoc_end = 120695150
    | Mm_Uniprot = Q7TPC7
  }}
}}
'''Eukaryotic elongation factor-2 kinase''', also known as '''EEF2K''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: EEF2K eukaryotic elongation factor-2 kinase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29904| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
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.<ref name="entrez"/><ref name=Ryazanov_1990>{{cite journal | vauthors = Ryazanov AG, Spirin AS | title = Phosphorylation of elongation factor 2: a key mechanism regulating gene expression in vertebrates | journal = The New Biologist | volume = 2 | issue = 10 | pages = 843–50 | date = Oct 1990 | pmid = 1964087 }}</ref>
{{PBB_Summary
| section_title =
| summary_text = This gene encodes a highly conserved protein kinase in the calmodulin-mediated signaling pathway that links activation of cell surface receptors to cell division. This kinase is involved in the regulation of protein synthesis. It phosphorylates eukaryotic elongation factor 2 (EEF2) and thus inhibits the EEF2 function. The activity of this kinase is increased in many cancers and may be a valid target for anti-cancer treatment.<ref name="entrez">{{cite web | title = Entrez Gene: EEF2K eukaryotic elongation factor-2 kinase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29904| accessdate = }}</ref>
}}


==References==
== Activation ==
{{reflist|2}}
 
==Further reading==
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.<ref name="Tavares_2012">{{cite journal | vauthors = 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 | title = Calcium/calmodulin stimulates the autophosphorylation of elongation factor 2 kinase on Thr-348 and Ser-500 to regulate its activity and calcium dependence | journal = Biochemistry | volume = 51 | issue = 11 | pages = 2232–45 | date = Mar 2012 | pmid = 22329831 | doi = 10.1021/bi201788e | pmc=3401519}}</ref><ref name="tavares 2014">{{cite journal | vauthors = Tavares CD, Ferguson SB, Giles DH, Wang Q, Wellmann RM, O'Brien JP, Warthaka M, Brodbelt JS, Ren P, Dalby KN | title = The molecular mechanism of eukaryotic elongation factor 2 kinase activation | journal = The Journal of Biological Chemistry | volume = 289 | issue = 34 | pages = 23901–16 | date = Aug 2014 | pmid = 25012662 | doi = 10.1074/jbc.m114.577148 | pmc=4156036}}</ref> 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.<ref name="tavares 2014" />
{{refbegin | 2}}
 
{{PBB_Further_reading
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.<ref name="Tavares_2012" />
| citations =
 
*{{cite journal | author=Nairn AC, Palfrey HC |title=Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2. |journal=J. Biol. Chem. |volume=262 |issue= 36 |pages= 17299-303 |year= 1988 |pmid= 3693353 |doi= }}
== Clinical significance ==
*{{cite journal | author=Redpath NT, Price NT, Severinov KV, Proud CG |title=Regulation of elongation factor-2 by multisite phosphorylation. |journal=Eur. J. Biochem. |volume=213 |issue= 2 |pages= 689-99 |year= 1993 |pmid= 8386634 |doi= }}
 
*{{cite journal  | author=Ryazanov AG, Ward MD, Mendola CE, ''et al.'' |title=Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 10 |pages= 4884-9 |year= 1997 |pmid= 9144159 |doi= }}
The activity of this kinase is increased in many cancers and may be a valid target for anti-cancer treatment.<ref name="entrez">{{cite web | title = Entrez Gene: EEF2K eukaryotic elongation factor-2 kinase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=29904| accessdate = }}</ref><ref name="pmid23706743">{{cite journal | vauthors = 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 | title = The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation | journal = Cell | volume = 153 | issue = 5 | pages = 1064–79 | date = May 2013 | pmid = 23706743 | doi = 10.1016/j.cell.2013.04.055 | pmc=4395874}}</ref>
*{{cite journal  | author=Pavur KS, Petrov AN, Ryazanov AG |title=Mapping the functional domains of elongation factor-2 kinase. |journal=Biochemistry |volume=39 |issue= 40 |pages= 12216-24 |year= 2000 |pmid= 11015200 |doi=  }}
 
*{{cite journal  | author=Diggle TA, Subkhankulova T, Lilley KS, ''et al.'' |title=Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/calmodulin-independent activity. |journal=Biochem. J. |volume=353 |issue= Pt 3 |pages= 621-6 |year= 2001 |pmid= 11171059 |doi=  }}
It is also suggested that eEF-2K may play a role the rapid anti-depressant effects of [[Ketamine#Depression|ketamine]] through its regulation of neuronal protein synthesis.<ref name=Monteggia_2013>{{cite journal | vauthors = Monteggia LM, Gideons E, Kavalali ET | title = The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine | journal = Biological Psychiatry | volume = 73 | issue = 12 | pages = 1199–203 | date = Jun 2013 | pmid = 23062356 | doi = 10.1016/j.biopsych.2012.09.006 | pmc=3574622}}</ref>
*{{cite journal  | author=Knebel A, Morrice N, Cohen P |title=A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. |journal=EMBO J. |volume=20 |issue= 16 |pages= 4360-9 |year= 2001 |pmid= 11500363 |doi= 10.1093/emboj/20.16.4360 }}
{{clear}}
*{{cite journal | author=Wang X, Li W, Williams M, ''et al.'' |title=Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. |journal=EMBO J. |volume=20 |issue= 16 |pages= 4370-9 |year= 2001 |pmid= 11500364 |doi= 10.1093/emboj/20.16.4370 }}
 
*{{cite journal  | author=Arora S, Yang JM, Craft J, Hait W |title=Detection of anti-elongation factor 2 kinase (calmodulin-dependent protein kinase III) antibodies in patients with systemic lupus erythematosus. |journal=Biochem. Biophys. Res. Commun. |volume=293 |issue= 3 |pages= 1073-6 |year= 2002 |pmid= 12051769 |doi= 10.1016/S0006-291X(02)00324-8 }}
== Cancer ==
*{{cite journal | author=Wistow G, Bernstein SL, Wyatt MK, ''et al.'' |title=Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants. |journal=Mol. Vis. |volume=8 |issue= |pages= 205-20 |year= 2002 |pmid= 12107410 |doi= }}
eEF-2K expression is often upregulated in cancer cells, including breast and pancreatic cancers and promotes cell proliferation, survival, motility/migration, invasion and tumorigenesis.<ref name="Tekedereli 2012">{{cite journal |vauthors= Tekedereli I, Alpay SN, Tavares CD, Cobanoglu ZE, Kaoud TS, Sahin I, Sood AK, Lopez-Berestein G, Dalby KN, Ozpolat B |title= Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer. |journal= PLoS One |volume= 7 |issue=7 |page= e41171 |date= Mar 20, 2012 |pmid= 22911754 |doi= 10.1371/journal.pone.0041171 }}</ref><ref name="ashour 2014">{{cite journal|last=|first=|date=Jan 22, 2014|title=Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells.|url=|journal=Apoptosis|volume=19|issue=1|pages=241-58|doi=10.1007/s10495-013-0927-2|pmid=24193916|via=|vauthors=Ashour AA, Abdel-Aziz AA, Mansour AM, Alpay SN, Huo L, Ozpolat B}}</ref>
*{{cite journal  | author=Knebel A, Haydon CE, Morrice N, Cohen P |title=Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways. |journal=Biochem. J. |volume=367 |issue= Pt 2 |pages= 525-32 |year= 2002 |pmid= 12171600 |doi= 10.1042/BJ20020916 }}
 
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
== References ==
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
{{reflist|33em}}
*{{cite journal | author=Browne GJ, Finn SG, Proud CG |title=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. |journal=J. Biol. Chem. |volume=279 |issue= 13 |pages= 12220-31 |year= 2004 |pmid= 14709557 |doi= 10.1074/jbc.M309773200 }}
 
*{{cite journal | author=Browne GJ, Proud CG |title=A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. |journal=Mol. Cell. Biol. |volume=24 |issue= 7 |pages= 2986-97 |year= 2004 |pmid= 15024086 |doi= }}
== Further reading ==
*{{cite journal | author=Brill LM, Salomon AR, Ficarro SB, ''et al.'' |title=Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry. |journal=Anal. Chem. |volume=76 |issue= 10 |pages= 2763-72 |year= 2004 |pmid= 15144186 |doi= 10.1021/ac035352d }}
{{refbegin|33em}}
*{{cite journal | author=Li X, Alafuzoff I, Soininen H, ''et al.'' |title=Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. |journal=FEBS J. |volume=272 |issue= 16 |pages= 4211-20 |year= 2005 |pmid= 16098202 |doi= 10.1111/j.1742-4658.2005.04833.x }}
* {{cite journal | vauthors = Nairn AC, Palfrey HC | title = Identification of the major Mr 100,000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2 | journal = The Journal of Biological Chemistry | volume = 262 | issue = 36 | pages = 17299–303 | date = Dec 1987 | pmid = 3693353 | doi = }}
*{{cite journal | author=Kimura K, Wakamatsu A, Suzuki Y, ''et al.'' |title=Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. |journal=Genome Res. |volume=16 |issue= 1 |pages= 55-65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406 }}
* {{cite journal | vauthors = Redpath NT, Price NT, Severinov KV, Proud CG | title = Regulation of elongation factor-2 by multisite phosphorylation | journal = European Journal of Biochemistry / FEBS | volume = 213 | issue = 2 | pages = 689–99 | date = Apr 1993 | pmid = 8386634 | doi = 10.1111/j.1432-1033.1993.tb17809.x }}
*{{cite journal | author=Hait WN, Wu H, Jin S, Yang JM |title=Elongation factor-2 kinase: its role in protein synthesis and autophagy. |journal=Autophagy |volume=2 |issue= 4 |pages= 294-6 |year= 2007 |pmid= 16921268 |doi= }}
* {{cite journal | vauthors = Pavur KS, Petrov AN, Ryazanov AG | title = Mapping the functional domains of elongation factor-2 kinase | journal = Biochemistry | volume = 39 | issue = 40 | pages = 12216–24 | date = Oct 2000 | pmid = 11015200 | doi = 10.1021/bi0007270 }}
*{{cite journal | author=Beausoleil SA, Villén J, Gerber SA, ''et al.'' |title=A probability-based approach for high-throughput protein phosphorylation analysis and site localization. |journal=Nat. Biotechnol. |volume=24 |issue= 10 |pages= 1285-92 |year= 2006 |pmid= 16964243 |doi= 10.1038/nbt1240 }}
* {{cite journal | vauthors = Diggle TA, Subkhankulova T, Lilley KS, Shikotra N, Willis AE, Redpath NT | title = Phosphorylation of elongation factor-2 kinase on serine 499 by cAMP-dependent protein kinase induces Ca2+/calmodulin-independent activity | journal = The Biochemical Journal | volume = 353 | issue = Pt 3 | pages = 621–6 | date = Feb 2001 | pmid = 11171059 | pmc = 1221608 | doi = 10.1042/0264-6021:3530621 }}
*{{cite journal  | author=Olsen JV, Blagoev B, Gnad F, ''et al.'' |title=Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. |journal=Cell |volume=127 |issue= 3 |pages= 635-48 |year= 2006 |pmid= 17081983 |doi= 10.1016/j.cell.2006.09.026 }}
* {{cite journal | vauthors = Knebel A, Morrice N, Cohen P | title = A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta | journal = The EMBO Journal | volume = 20 | issue = 16 | pages = 4360–9 | date = Aug 2001 | pmid = 11500363 | pmc = 125581 | doi = 10.1093/emboj/20.16.4360 }}
}}
* {{cite journal | vauthors = Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG | title = Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase | journal = The EMBO Journal | volume = 20 | issue = 16 | pages = 4370–9 | date = Aug 2001 | pmid = 11500364 | pmc = 125559 | doi = 10.1093/emboj/20.16.4370 }}
* {{cite journal | vauthors = Arora S, Yang JM, Craft J, Hait W | title = Detection of anti-elongation factor 2 kinase (calmodulin-dependent protein kinase III) antibodies in patients with systemic lupus erythematosus | journal = Biochemical and Biophysical Research Communications | volume = 293 | issue = 3 | pages = 1073–6 | date = May 2002 | pmid = 12051769 | doi = 10.1016/S0006-291X(02)00324-8 }}
* {{cite journal | vauthors = Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K | title = Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants | journal = Molecular Vision | volume = 8 | issue = | pages = 205–20 | date = Jun 2002 | pmid = 12107410 | doi = }}
* {{cite journal | vauthors = Knebel A, Haydon CE, Morrice N, Cohen P | title = Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways | journal = The Biochemical Journal | volume = 367 | issue = Pt 2 | pages = 525–32 | date = Oct 2002 | pmid = 12171600 | pmc = 1222910 | doi = 10.1042/BJ20020916 }}
* {{cite journal | vauthors = Browne GJ, Finn SG, Proud CG | title = 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 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 13 | pages = 12220–31 | date = Mar 2004 | pmid = 14709557 | doi = 10.1074/jbc.M309773200 }}
* {{cite journal | vauthors = Browne GJ, Proud CG | title = A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin | journal = Molecular and Cellular Biology | volume = 24 | issue = 7 | pages = 2986–97 | date = Apr 2004 | pmid = 15024086 | pmc = 371112 | doi = 10.1128/MCB.24.7.2986-2997.2004 }}
* {{cite journal | vauthors = Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC | title = Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry | journal = Analytical Chemistry | volume = 76 | issue = 10 | pages = 2763–72 | date = May 2004 | pmid = 15144186 | doi = 10.1021/ac035352d }}
* {{cite journal | vauthors = Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ | title = Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain | journal = The FEBS Journal | volume = 272 | issue = 16 | pages = 4211–20 | date = Aug 2005 | pmid = 16098202 | doi = 10.1111/j.1742-4658.2005.04833.x }}
* {{cite journal | vauthors = 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 | title = Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes | journal = Genome Research | volume = 16 | issue = 1 | pages = 55–65 | date = Jan 2006 | pmid = 16344560 | pmc = 1356129 | doi = 10.1101/gr.4039406 }}
* {{cite journal | vauthors = Hait WN, Wu H, Jin S, Yang JM | title = Elongation factor-2 kinase: its role in protein synthesis and autophagy | journal = Autophagy | volume = 2 | issue = 4 | pages = 294–6 | year = 2007 | pmid = 16921268 | doi = 10.4161/auto.2857 }}
* {{cite journal | vauthors = Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP | title = A probability-based approach for high-throughput protein phosphorylation analysis and site localization | journal = Nature Biotechnology | volume = 24 | issue = 10 | pages = 1285–92 | date = Oct 2006 | pmid = 16964243 | doi = 10.1038/nbt1240 }}
* {{cite journal | vauthors = Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M | title = Global, in vivo, and site-specific phosphorylation dynamics in signaling networks | journal = Cell | volume = 127 | issue = 3 | pages = 635–48 | date = Nov 2006 | pmid = 17081983 | doi = 10.1016/j.cell.2006.09.026 }}
{{refend}}
{{refend}}


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[[Category:EC 2.7.11]]

Latest revision as of 09:25, 10 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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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

  1. ↑ "EEF2K Gene (Protein Coding)". GeneCards. Weizmann Institute of Science. Retrieved 4 November 2015. 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. ↑ 2.0 2.1 2.2 "Entrez Gene: EEF2K eukaryotic elongation factor-2 kinase".
  3. ↑ 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". Proceedings of the National Academy of Sciences of the United States of America. 94 (10): 4884–9. doi:10.1073/pnas.94.10.4884. PMC 24600. PMID 9144159.
  4. ↑ 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.
  5. ↑ 5.0 5.1 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 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. PMC 3401519. PMID 22329831.
  6. ↑ 6.0 6.1 Tavares CD, Ferguson SB, Giles DH, Wang Q, Wellmann RM, O'Brien JP, Warthaka M, Brodbelt JS, Ren P, Dalby KN (Aug 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. PMC 4156036. PMID 25012662.
  7. ↑ 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. PMC 4395874. PMID 23706743.
  8. ↑ Monteggia LM, Gideons E, Kavalali ET (Jun 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. PMC 3574622. PMID 23062356.
  9. ↑ Tekedereli I, Alpay SN, Tavares CD, Cobanoglu ZE, Kaoud TS, Sahin I, Sood AK, Lopez-Berestein G, Dalby KN, Ozpolat B (Mar 20, 2012). "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. doi:10.1371/journal.pone.0041171. PMID 22911754.
  10. ↑ Ashour AA, Abdel-Aziz AA, Mansour AM, Alpay SN, Huo L, Ozpolat B (Jan 22, 2014). "Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells". Apoptosis. 19 (1): 241–58. doi:10.1007/s10495-013-0927-2. PMID 24193916.

Further reading

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