Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases

Abstract

Eukaryotic elongation factor 2 kinase (eEF2K) is an unusual protein kinase that regulates the elongation stage of protein synthesis by phosphorylating and inhibiting its only known substrate, eEF2. Elongation is a highly energy-consuming process, and eEF2K activity is tightly regulated by several signaling pathways. Regulating translation elongation can modulate the cellular energy demand and may also control the expression of specific proteins. Growing evidence links eEF2K to a range of human diseases, including cardiovascular conditions (atherosclerosis, via macrophage survival) and pulmonary arterial hypertension, as well as solid tumors, where eEF2K appears to play contrasting roles depending on tumor type and stage. eEF2K is also involved in neurological disorders and may be a valuable target in treating depression and certain neurodegenerative diseases. Because eEF2K is not required for mammalian development or cell viability, inhibiting its function may not elicit serious side effects, while the fact that it is an atypical kinase and quite distinct from the vast majority of other mammalian kinases suggests the possibility to develop it into compounds that inhibit eEF2K without affecting other important protein kinases. Further research is needed to explore these possibilities and there is an urgent need to identify and characterize potent and specific small-molecule inhibitors of eEF2K. In this article we review the recent evidence concerning the role of eEF2K in human diseases as well as the progress in developing small-molecule inhibitors of this enzyme.

Intrauterine growth restriction inhibits expression of eukaryotic elongation factor 2 kinase, a regulator of protein translation

“…Similar findings have also been reported for the human IUGR placenta (12,74). The role of eEF2K in adapting cell growth to nutrient deprivation has gotten considerable attention recently as an approach to treating cancer (49,68). Some forms of cancer cells appear to adapt to their nutrient-limiting environment by inhibiting eEF2K activity at the posttranslational level (18,70).…”

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

“…In this study, we show that eEF2K activating pathways such as mTORC1 inhibition, AMPK, or the ISR were not involved in NFR-mediated eEF2K activation. Possible alternative pathway that could contribute to NFR-mediated effects includes calcium ion influx, hypoxia, or ERK signaling, which have been proposed to regulate eEF2K [44]. It ◀ Figure 5.…”

Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex

“…eEF2K is a Ca2þ/ calmodulin-dependent serine/threonine kinase important for the regulation of elongation of protein translation (Monteggia et al, 2013). Elongation is a highly energy-consuming process, and eEF2K activity is tightly regulated by several signaling pathways (Liu and Proud, 2016). eEF2K is expressed in neurons, and recent evidence suggests that it may play a role in processes such as learning and memory and in depression (Liu and Proud, 2016).…”

“…Elongation is a highly energy-consuming process, and eEF2K activity is tightly regulated by several signaling pathways (Liu and Proud, 2016). eEF2K is expressed in neurons, and recent evidence suggests that it may play a role in processes such as learning and memory and in depression (Liu and Proud, 2016). In fact, Park et al (2008) showed that eEF2K plays an important role in the synthesis of Arc/Arg3.1, a protein involved in neurotransmitter receptor trafficking and in long-term depression, a process that reflects changes in synaptic strength.…”