Disease relevance of EEF2K

• To localize the functional domains of eEF-2 kinase, we expressed human eEF-2 kinase in Escherichia coli as a GST-tagged fusion protein, and then performed systematic in vitro deletion mutagenesis [1].
• Hypoxia Inhibits Protein Synthesis through a 4E-BP1 and Elongation Factor 2 Kinase Pathway Controlled by mTOR and Uncoupled in Breast Cancer Cells [2].
• Gene silencing of 4E-BP1 and eEF2 kinase or TSC2 confers resistance to hypoxia inhibition of protein synthesis in immortalized breast epithelial cells [2].
• The activity of eEF-2 kinase is increased in glioblastoma and other malignancies, yet its role in neoplasia is uncertain [3].
• Forced overexpression of eEF-2 kinase in a glioma cell line produced 10-fold resistance to NH125 [4].

Psychiatry related information on EEF2K

• Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain [5].

High impact information on EEF2K

• A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta [6].
• The phosphorylation of eEF2K at Ser359 was also induced by insulin-like growth factor-1 [6].
• Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase [7].
• Mutation of this site to alanine strongly attenuates the effects of insulin and rapamycin both on the binding of calmodulin to eEF2 kinase and on eEF2 kinase activity [8].
• In contrast, overexpression of eEF-2 kinase increased autophagy [3].

Biological context of EEF2K

• The amino acid sequence of the carboxyl-terminal domain of eEF-2 kinase displays similarity to several proteins, all of which contain repeats of a 36-amino acid motif that we named "motif 36" [1].
• Knockdown of eEF-2 kinase by RNA interference inhibited autophagy in glioblastoma cell lines, as measured by light chain 3 (LC3)-II formation, acidic vesicular organelle staining, and electron microscopy [3].
• Given that eEF2 phosphorylation inhibits eEF2 activity and mRNA translation, these findings suggest that the inhibition of protein synthesis in contracting skeletal muscle is due to the Ca(2)(+)-induced stimulation of eEF2 kinase [9].
• Cloning and sequencing of eEF-2 kinase led to the discovery of a new family of protein kinases, named alpha-kinases, whose catalytic domains display no sequence homology to conventional eukaryotic protein kinases [10].
• Rapid changes in the activity and abundance of eEF-2 kinase have been observed on growth stimulation, and increased enzyme activity is characteristic of malignant cell growth [11].

Anatomical context of EEF2K

• Furthermore, elevation of cAMP levels in adipocytes also increases the level of Ca(2+)/CaM-independent eEF-2K activity to a similar extent, providing a mechanistic link between elevated cAMP and the inhibition of protein synthesis [Diggle, Redpath, Heesom and Denton (1998) Biochem. J. 336, 525-529] [12].
• In the growth cone, calcium elevation increased eEF2 kinase (EF2K), a calcim-calmodulin-dependent enzyme [13].
• Incubation of purified eEF-2 kinase with a source of ubiquitination enzymes (rabbit reticulocyte lysate), purified ubiquitin, and ATP revealed the presence of increasing molecular weight species of ubiquitinated eEF-2 kinase [11].
• In this paper, we establish the presence of Ca2+/calmodulin-dependent kinase III or eEF-2 kinase in these oocytes and describe how the protein synthesis inhibitor emetine is able to release them from the metaphase block [14].
• Knockdown of eEF-2 kinase by RNA interference inhibited autophagy in several cell types as measured by light chain 3 (LC3)-II formation, acidic vesicular organelle staining, and electron microscopy [15].

Associations of EEF2K with chemical compounds

• In the present study we have examined the effects of the protein synthesis inhibitor anisomycin and tumour necrosis factor-alpha (TNF-alpha) on the phosphorylation of eEF2 kinase [16].
• Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways [16].
• It is one of the unconventional eukaryotic protein kinases with respect to its structural domains in comparison to other members of the serine/threonine protein kinase superfamily. eEF-2K is highly conserved in nature [17].
• Likewise, treatment of cells with the inhibitor rottlerin did not block the stimulatory effect of EtOH on eEF2, suggesting that eEF2 kinase (eEF2K) does not play a role in regulating eEF2 [18].
• However, skeletal muscle eEF2 kinase was potently activated by Ca(2)(+)-calmodulin in vitro, suggesting that the higher eEF2 phosphorylation in working skeletal muscle is mediated by allosteric activation of eEF2 kinase by Ca(2)(+) signalling via calmodulin [9].

Enzymatic interactions of EEF2K

• Our recent studies have also identified the mechanism by which mTOR signalling regulates the phosphorylation of eEF2. eEF2 kinase is phosphorylated by p70 S6 kinase at Ser-366; this results in the inactivation of eEF2 kinase, especially at low (micromolar) Ca concentrations [19].

Regulatory relationships of EEF2K

• Since the phosphorylation of Ser-377 does not inhibit eEF2 kinase in vitro, our results suggest that anisomycin or TNF-alpha inhibit eEF2 kinase via the phosphorylation of Ser-359 [16].

Other interactions of EEF2K

• Paradoxically, activation of eEF2 kinase (eEF2K), the only known kinase that regulates eEF2, was observed only at 12 hours after SCH66336 treatment [20].
• Calmodulin-dependent protein kinase III (CaM kinase III, elongation factor-2 kinase) is a unique member of the Ca2+/CaM-dependent protein kinase family [21].
• Furthermore, inhibition of eEF2-kinase prevented the forskolin-mediated down-regulation of cyclin D3 [22].

Analytical, diagnostic and therapeutic context of EEF2K

• Endoproteinase Arg-C digestion of GST-eEF-2K produced two phosphopeptides that were separated by HPLC and sequenced [12].

References