title: Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy.
abstract: Eukaryotic elongation factor 2 kinase (eEF2K) inhibits the elongation stage of protein synthesis by phosphorylating its only known substrate, eEF2. eEF2K is tightly regulated by nutrient-sensitive signalling pathways. For example, it is inhibited by signalling through mammalian target of rapamycin complex 1 (mTORC1). It is therefore activated under conditions of nutrient deficiency. Here we show that inhibiting eEF2K or knocking down its expression renders cancer cells sensitive to death under nutrient-starved conditions, and that this is rescued by compounds that block protein synthesis. This implies that eEF2K protects nutrient-deprived cells by inhibiting protein synthesis. Cells in which signalling through mTORC1 is highly active are very sensitive to nutrient withdrawal. Inhibiting mTORC1 protects them. Our data reveal that eEF2K makes a substantial contribution to the cytoprotective effect of mTORC1 inhibition. eEF2K is also reported to promote another potentially cytoprotective process, autophagy. We have used several approaches to test whether inhibition or loss of eEF2K affects autophagy under a variety of conditions. We find no evidence that eEF2K is involved in the activation of autophagy in the cell types we have studied. We conclude that eEF2K protects cancer cells against nutrient starvation by inhibiting protein synthesis rather than by activating autophagy.
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom; South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA5000, Australia.
authors.forename: Claire E J
authors.initials: CE
authors.lastname: Moore
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom; South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA5000, Australia; School of Biological Sciences, University of Adelaide, Adelaide SA5005, Australia.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom; South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA5000, Australia.
authors.forename: Jianling
authors.initials: J
authors.lastname: Xie
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom.
authors.forename: Jo
authors.initials: J
authors.lastname: Pickford
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Barron
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom.
authors.forename: Sergio
authors.initials: S
authors.lastname: Regufe da Mota
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Matthias
authors.initials: M
authors.lastname: Versele
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom; South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA5000, Australia; School of Biological Sciences, University of Adelaide, Adelaide SA5005, Australia. Electronic address: Christopher.Proud@sahmri.com.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
mesh_terms: D000818:Animals; D001343:Autophagy; D002470:Cell Survival; D054736:Elongation Factor 2 Kinase / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C517690:Eef2k protein, mouse; D054736:Elongation Factor 2 Kinase
keywords: Glucose starvation; Translation; eEF2K