Skip to main content
SpringerLink
Log in

Eukaryotic elongation factor-2 kinase (eEF2K): a potential therapeutic target in cancer

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Eukaryotic elongation factor-2 kinase (eEF2K), encoded by the EEF2K gene, is well-known to be a Ca2+/calmodulin (CaM)-dependent kinase which can negatively modulate protein synthesis. It is highly conserved among eukaryotes from mammals to invertebrates, of which human and mouse may have 99 % overall amino acid identity. This kinase can phosphorylate eukaryotic elongation factor-2 (eEF2) or undergo the process of autophosphorylation at multiple sites to inhibit its function in translation elongation. Due to the fact that regulation of eEF2 by eEF2K is an evolutionarily conserved mechanism, eEF2K activity may confer tumor cell adaption to metabolic stress under acute nutrient depletion, and the high expressed level of eEF2K has been found in several types of malignancies. eEF2K may modulate the expression of some apoptotic proteins such as XIAP, c-FLIPL, Bcl-XL, PI3KCI and p70S6K to inhibit apoptotic process in cancer. On the other hand, it plays a regulatory role in autophagy involved in mTORC1, AMPK and Atg8, thereby promoting cancer cell survival. Additionally, eEF2K may play a crucial role in the crosstalk between apoptosis and autophagy in cancer. Collectively, these findings have led to the conclusions that eEF2K may contribute to carcinogenesis, and thus being utilized as a potential target for future cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ryazanov AG (2002) Elongation factor-2 kinase and its newly discovered relatives. FEBS Lett 514:26–29

    Article  PubMed  CAS  Google Scholar 

  2. Nairn AC, Matsushita M, Nastiuk K, Horiuchi A, Mitsui K, Shimizu Y et al (2001) Elongation factor-2 phosphorylation and the regulation of protein synthesis by calcium. Prog Mol Subcell Biol 27:91–129

    Article  PubMed  CAS  Google Scholar 

  3. Nairn AC, Picciotto MR (1994) Calcium/calmodulin-dependent protein kinases. Semin Cancer Biol 5:295–303

    PubMed  CAS  Google Scholar 

  4. White-Gilbertson S, Kurtz DT, Voelkel-Johnson C (2009) The role of protein synthesis in cell cycling and cancer. Mol Oncol 3:402–408

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  PubMed  CAS  Google Scholar 

  6. Ryazanov AG, Natapov PG, Shestakova EA, Severin FF, Spirin AS (1988) Phosphorylation of the elongation factor 2: the fifth Ca2+/calmodulin-dependent system of protein phosphorylation. Biochimie 70:619–626

    Article  PubMed  CAS  Google Scholar 

  7. Ye Q, Crawley SW, Yang Y, Côté GP, Jia Z (2010) Crystal structure of the alpha-kinase domain of Dictyostelium myosin heavy chain kinase A. Sci Signal 3:ra17

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pigott CR, Mikolajek H, Moore CE, Finn SJ, Phippen CW, Werner JM et al (2012) Insights into the regulation of eukaryotic elongation factor 2 kinase and the interplay between its domains. Biochem J 442:105–118

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Pavur KS, Petrov AN, Ryazanov AG (2000) Mapping the functional domains of elongation factor-2 kinase. Biochemistry 39:12216–12224

    Article  PubMed  CAS  Google Scholar 

  10. Carlberg U, Nilsson A, Nygård O (1990) Functional properties of phosphorylated elongation factor 2. Eur J Biochem 191:639–645

    Article  PubMed  CAS  Google Scholar 

  11. Heise C, Gardoni F, Culotta L, di Luca M, Verpelli C, Sala C (2014) Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons. Front Cell Neurosci 8:35

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chu HP, Liao Y, Novak JS, Hu Z, Merkin JJ, Shymkiv Y et al (2014) Germline quality control: eEF2 K stands guard to eliminate defective oocytes. Dev Cell 28:561–572

    Article  PubMed  CAS  Google Scholar 

  13. 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 353:621–626

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Pyr Dit Ruys S, Wang X, Smith EM, Herinckx G, Hussain N, Rider MH et al (2012) Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase. Biochem J 442:681–692

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo AR, Kool M et al (2013) The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153:1064–1079

    Article  PubMed  CAS  Google Scholar 

  16. Liu JJ, Lin M, Yu JY, Liu B, Bao JK (2011) Targeting apoptotic and autophagic pathways for cancer therapeutics. Cancer Lett 300:105–114

    Article  PubMed  CAS  Google Scholar 

  17. Zhang Y, Cheng Y, Zhang L, Ren X, Huber-Keener KJ, Lee S et al (2011) Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-XL expression. Biochem Biophys Res Commun 414:129–134

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Ashour AA, Abdel-Aziz AA, Mansour AM, Alpay SN, Huo L, Ozpolat B (2014) Targeting elongation factor-2 kinase (eEF-2 K) induces apoptosis in human pancreatic cancer cells. Apoptosis 19:241–258

    Article  PubMed  CAS  Google Scholar 

  19. Liu B, Wen X, Cheng Y (2013) Survival or death: disequilibrating the oncogenic and tumor suppressive autophagy in cancer. Cell Death Dis 4:e892

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Hait WN, Wu H, Jin S, Yang JM (2006) Elongation factor-2 kinase: its role in protein synthesis and autophagy. Autophagy 2:294–296

    Article  PubMed  CAS  Google Scholar 

  21. Cheng Y, Li H, Ren X, Niu T, Hait WN, Yang J (2010) Cytoprotective effect of the elongation factor-2 kinase-mediated autophagy in breast cancer cells subjected to growth factor inhibition. PLoS ONE 5:e9715

    Article  PubMed  PubMed Central  Google Scholar 

  22. Cheng Y, Ren X, Zhang Y, Shan Y, Huber-Keener KJ, Zhang L et al (2013) Integrated regulation of autophagy and apoptosis by EEF2 K controls cellular fate and modulates the efficacy of curcumin and velcade against tumor cells. Autophagy 9:208–219

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Devkota AK, Warthaka M, Edupuganti R, Tavares CD, Johnson WH, Ozpolat B et al (2014) High-throughput screens for eEF-2 kinase. J Biomol Screen 19:445–452

    Article  PubMed  Google Scholar 

  24. Wu H, Zhu H, Liu DX, Niu TK, Ren X, Patel R et al (2009) Silencing of elongation factor-2 kinase potentiates the effect of 2-deoxy-d-glucose against human glioma cells through blunting of autophagy. Cancer Res 69:2453–2460

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Cheng Y, Yan L, Ren X, Yang JM (2011) eEF-2 kinase, another meddler in the “yin and yang” of Akt-mediated cell fate. Autophagy 7:660–661

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Chen Z, Gopalakrishnan SM, Bui MH, Soni NB, Warrior U, Johnson EF et al (2011) 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2): a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor. J Biol Chem 286:43951–43958

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Ren H, Tai SK, Khuri F, Chu Z, Mao L (2005) Farnesyltransferase inhibitor SCH66336 induces rapid phosphorylation of eukaryotic translation elongation factor 2 in head and neck squamous cell carcinoma cells. Cancer Res 65:5841–5847

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grants from the Key Projects of the National Science and Technology Pillar Program (No. 2012BAI30B02), and the National Natural Science Foundation of China (Nos. 81160543, 81172374, 81260628 and 81303270).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China

    L. L. Fu, T. Xie, S. Y. Zhang & B. Liu

Authors
  1. L. L. Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Y. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Liu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, L.L., Xie, T., Zhang, S.Y. et al. Eukaryotic elongation factor-2 kinase (eEF2K): a potential therapeutic target in cancer. Apoptosis 19, 1527–1531 (2014). https://doi.org/10.1007/s10495-014-1019-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-014-1019-7

Keywords

Search

Navigation