Abstract
Eukaryotic elongation factor 2 kinase (eEF2K) is a highly unusual protein kinase that negatively regulates the elongation step of protein synthesis. This step uses the vast majority of the large amount of energy and amino acids required for protein synthesis. eEF2K activity is controlled by an array of regulatory inputs, including inhibition by signalling through mammalian target of rapamycin complex 1 (mTORC1). eEF2K is activated under conditions of stress, such as energy depletion or nutrient deprivation, which can arise in poorly-vascularised tumours. In many such stress conditions, eEF2K exerts cytoprotective effects. A growing body of data indicates eEF2K aids the growth of solid tumours in vivo. Since eEF2K is not essential (in mice) under ‘normal’ conditions, eEF2K may be a useful target in the treatment of solid tumours. However, some reports suggest that eEF2K may actually impair tumorigenesis in some situations. Such a dual role of eEF2K in cancer would be analogous to the situation for other pathways involved in cell metabolism, such as autophagy and mTORC1. Further studies are needed to define the role of eEF2K in different tumour types and at differing stages in tumorigenesis, and to assess its utility as a therapeutic target in oncology.
Highlights
Introduction toeEF2KEukaryotic elongation factor 2 kinase is an atypical protein kinase that phosphorylates and inactivates eEF2, the protein that helps ribosomes move along mRNAs during the elongation stage of protein synthesis
This possibility ‘makes sense’ at several levels: eEF2K and autophagy are both negatively regulated by mammalian target of rapamycin complex 1 (mTORC1); protein synthesis is a major user of amino acids that can be generated by autophagy; and eEF2K negatively regulates an anabolic process, so it would be logical that it positively regulates a catabolic one
It seems clear that eEF2K generally acts to protect cancer cells against stresses such as nutrient deprivation, it is still unclear how it does this
Summary
Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) is an atypical protein kinase that phosphorylates and inactivates eEF2, the protein that helps ribosomes move along mRNAs during the elongation stage of protein synthesis (mRNA translation; reviewed [1,2]). EEF2K is a negative regulator of the elongation stage of protein synthesis; this is the stage that consumes almost all (>99%) of the energy (ATP and GTP) and amino acids used by protein synthesis. The addition of each amino acid requires two GTP molecules (used directly in elongation and hydrolysed to GDP) and one ATP (used in attaching amino acids to tRNAs, which is hydrolysed to AMP, i.e., the equivalent of two high energy bonds). Protein synthesis is a major part of the cellular energy economy, using up to 30–35% of total ATP (or equivalents)
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