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,[5] is an enzyme that in humans is encoded by the EEF2K gene.[6][7]

EEF2K
Identifiers
AliasesEEF2K, HSU93850, eEF-2K, eukaryotic elongation factor 2 kinase, CAMKIII, calmodulin-dependent protein kinase III
External IDsOMIM: 606968; MGI: 1195261; HomoloGene: 7299; GeneCards: EEF2K; OMA:EEF2K - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_013302

NM_001267710
NM_001267711
NM_007908

RefSeq (protein)

NP_037434

NP_001254639
NP_001254640
NP_031934

Location (UCSC)Chr 16: 22.21 – 22.29 MbChr 7: 120.44 – 120.51 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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.[6][8]

Activation

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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.[9][10] 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.[10]

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.[9]

Clinical significance

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The activity of this kinase is increased in many cancers and may be a valid target for anti-cancer treatment.[6][11]

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.[12]

Cancer

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eEF-2K expression is often upregulated in cancer cells, including breast and pancreatic cancers and promotes cell proliferation, survival, motility/migration, invasion and tumorigenesis.[13][14]

References

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  1. ^ a b c ENSG00000284161 GRCh38: Ensembl release 89: ENSG00000103319, ENSG00000284161Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035064Ensembl, 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. ^ "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
  6. ^ a b c "Entrez Gene: EEF2K eukaryotic elongation factor-2 kinase".
  7. ^ 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. Bibcode:1997PNAS...94.4884R. doi:10.1073/pnas.94.10.4884. PMC 24600. PMID 9144159.
  8. ^ 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.
  9. ^ a b 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.
  10. ^ a b 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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. Bibcode:2012PLoSO...741171T. doi:10.1371/journal.pone.0041171. PMC 3401164. PMID 22911754.
  14. ^ 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. S2CID 16393302.

Further reading

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