ArticleMolecular and cellular biology2015
Elongation Factor 2 Kinase Is Regulated by Proline Hydroxylation and Protects Cells during Hypoxia.
Article in Molecular and cellular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 73 citations in OpenAlex.
- Epigenetic alterations facilitate transcriptional and translational programs in hypoxia.Nature cell biology · 2025Article
- Hypoxia-mediated regulation of mRNA metabolism: from transcription to stability.Cell communication and signaling : CCS · 2025Review
- Eukaryotic Elongation Factor 2 Kinase EFK-1/eEF2K promotes starvation resistance by preventing oxidative damage in C. elegans.Nature communications · 2025Article
- Adaptation of Natural Killer Cells to Hypoxia: A Review of the Transcriptional, Translational, and Metabolic Processes.ImmunoTargets and therapy · 2025Review
- Elongation factor 2 in cancer: a promising therapeutic target in protein translation.Cellular & molecular biology letters · 2024Review
- The eEF2 kinase coordinates the DNA damage response to cisplatin by supporting p53 activation.Cell death & disease · 2024Article
- Revealing eEF-2 kinase: recent structural insights into function.Trends in biochemical sciences · 2024Review
- Identification ofmSphere · 2023Article
- Roles of eukaryotic elongation factor 2 kinase (eEF2K) in neuronal plasticity, cognition, and Alzheimer disease.Journal of neurochemistry · 2023Review
- Increased supply of methionine during a heat-stress challenge in lactating holstein cows alters mammary tissue mTOR signaling and its response to lipopolysaccharide.Journal of animal science · 2022Article
- Structural basis for the calmodulin-mediated activation of eukaryotic elongation factor 2 kinase.Science advances · 2022Article
- Hydroxyproline in animal metabolism, nutrition, and cell signaling.Amino acids · 2022Review
- Review
- TSC-insensitive Rheb mutations induce oncogenic transformation through a combination of constitutively active mTORC1 signalling and proteome remodelling.Cellular and molecular life sciences : CMLS · 2021Article
- Hypoxia/HIF Modulates Immune Responses.Biomedicines · 2021Review
- Progress in the Development of Eukaryotic Elongation Factor 2 Kinase (eEF2K) Natural Product and Synthetic Small Molecule Inhibitors for Cancer Chemotherapy.International journal of molecular sciences · 2021Review
- Cancer Plasticity: The Role of mRNA Translation.Trends in cancer · 2021Review
- Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia.Cancers · 2021Review
- Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase.Frontiers in molecular biosciences · 2021Review
- Influence of hypoxia on biochemical aspects and on expression of genes related to oxygen-homeostasis of the Amazonian cichlid Astronotus ocellatus (Agassiz, 1831).Genetics and molecular biology · 2021Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Protein synthesis, especially translation elongation, requires large amounts of energy, which is often generated by oxidative metabolism. Elongation is controlled by phosphorylation of eukaryotic elongation factor 2 (eEF2), which inhibits its activity and is catalyzed by eEF2 kinase (eEF2K), a calcium/calmodulin-dependent α-kinase. Hypoxia causes the activation of eEF2K and induces eEF2 phosphorylation independently of previously known inputs into eEF2K. Here, we show that eEF2K is subject to hydroxylation on proline-98. Proline hydroxylation is catalyzed by proline hydroxylases, oxygen-dependent enzymes which are inactivated during hypoxia. Pharmacological inhibition of proline hydroxylases also stimulates eEF2 phosphorylation. Pro98 lies in a universally conserved linker between the calmodulin-binding and catalytic domains of eEF2K. Its hydroxylation partially impairs the binding of calmodulin to eEF2K and markedly limits the calmodulin-stimulated activity of eEF2K. Neuronal cells depend on oxygen, and eEF2K helps to protect them from hypoxia. eEF2K is the first example of a protein directly involved in a major energy-consuming process to be regulated by proline hydroxylation. Since eEF2K is cytoprotective during hypoxia and other conditions of nutrient insufficiency, it may be a valuable target for therapy of poorly vascularized solid tumors.
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