Eukaryotic elongation factor-2 kinase (eEF-2 kinase oreEF-2K), also known ascalmodulin-dependent protein kinase III (CAMKIII) andcalcium/calmodulin-dependent eukaryotic elongation factor 2 kinase,[5] is anenzyme that in humans is encoded by theEEF2Kgene.[6][7]
eEF-2 kinase is a highly conservedprotein kinase in thecalmodulin-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]
The activity of eEF-2K is dependent on calcium andcalmodulin. 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]
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 ofketamine through its regulation of neuronal protein synthesis.[12]
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]
^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.PMID1964087.
^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.PMC4395874.PMID23706743.
Redpath NT, Price NT, Severinov KV, Proud CG (Apr 1993). "Regulation of elongation factor-2 by multisite phosphorylation".European Journal of Biochemistry.213 (2):689–99.doi:10.1111/j.1432-1033.1993.tb17809.x.PMID8386634.
Pavur KS, Petrov AN, Ryazanov AG (Oct 2000). "Mapping the functional domains of elongation factor-2 kinase".Biochemistry.39 (40):12216–24.doi:10.1021/bi0007270.PMID11015200.
Arora S, Yang JM, Craft J, Hait W (May 2002). "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.doi:10.1016/S0006-291X(02)00324-8.PMID12051769.
Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K (Jun 2002). "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.PMID12107410.
Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC (May 2004). "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.doi:10.1021/ac035352d.PMID15144186.
Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ (Aug 2005). "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.doi:10.1111/j.1742-4658.2005.04833.x.PMID16098202.S2CID43085490.
Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (Oct 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization".Nature Biotechnology.24 (10):1285–92.doi:10.1038/nbt1240.PMID16964243.S2CID14294292.
