Eukaryotic elongation factor 2 kinase regulates the cold stress response by slowing translation elongation

2015 ◽  
Vol 465 (2) ◽  
pp. 227-238 ◽  
Author(s):  
John R. P. Knight ◽  
Amandine Bastide ◽  
Anne Roobol ◽  
Jo Roobol ◽  
Thomas J. Jackson ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Stress Response ◽  
Cold Stress ◽  
Elongation Factor ◽  
Translation Elongation ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor

Modulation of translation elongation rates, and not initiation, is responsible for the reduction of protein synthesis in response to cold-stress induced in mild hypothermic conditions. This is mediated by release of Ca2+ ions from the endoplasmic reticulum (ER) and activation of eEF2K (eukaryotic elongation factor 2 kinase).

scholarly journals Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase

2021 ◽  
Vol 8 ◽  
Author(s):  
Darby J. Ballard ◽  
Hao-Yun Peng ◽  
Jugal Kishore Das ◽  
Anil Kumar ◽  
Liqing Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Elongation Factor ◽  
Protein Translation ◽  
Negative Regulator ◽  
Translation Elongation ◽  
Elongation Factor 2 ◽  
Global Rate ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor

Eukaryotic Elongation Factor-2 Kinase (eEF2K) acts as a negative regulator of protein synthesis, translation, and cell growth. As a structurally unique member of the alpha-kinase family, eEF2K is essential to cell survival under stressful conditions, as it contributes to both cell viability and proliferation. Known as the modulator of the global rate of protein translation, eEF2K inhibits eEF2 (eukaryotic Elongation Factor 2) and decreases translation elongation when active. eEF2K is regulated by various mechanisms, including phosphorylation through residues and autophosphorylation. Specifically, this protein kinase is downregulated through the phosphorylation of multiple sites via mTOR signaling and upregulated via the AMPK pathway. eEF2K plays important roles in numerous biological systems, including neurology, cardiology, myology, and immunology. This review provides further insights into the current roles of eEF2K and its potential to be explored as a therapeutic target for drug development.

Regulation and roles of elongation factor 2 kinase

2015 ◽  
Vol 43 (3) ◽  
pp. 328-332 ◽  
Author(s):  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Elongation Factor ◽  
Mrna Translation ◽  
Inhibit Protein Synthesis ◽  
Potential Therapeutic Target ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Nutrient Consumption ◽  
Almost All

Eukaryotic elongation factor 2 kinase (eEF2K) belongs to the small family of atypical protein kinases termed α-kinases, and is the only calcium/calmodulin (Ca/CaM)-dependent member of that group. It phosphorylates and inactivates eEF2, to slow down the rate of elongation, the stage in mRNA translation that consumes almost all the energy and amino acids consumed by protein synthesis. In addition to activation by Ca/CaM, eEF2K is also regulated by an array of other regulatory inputs, which include inhibition by the nutrient- and growth-factor activated signalling pathways. Recent evidence shows that eEF2K plays an important role in learning and memory, processes that require the synthesis of new proteins and involve Ca-mediated signalling. eEF2K is activated under conditions of nutrient and energy depletion. In cancer cells, or certain tumours, eEF2K exerts cytoprotective effects, which probably reflect its ability to inhibit protein synthesis, and nutrient consumption, under starvation conditions. eEF2K is being evaluated as a potential therapeutic target in cancer.

scholarly journals Identification of autophosphorylation sites in eukaryotic elongation factor-2 kinase

2012 ◽  
Vol 442 (3) ◽  
pp. 681-692 ◽  
Author(s):  
Sébastien Pyr Dit Ruys ◽  
Xuemin Wang ◽  
Ewan M. Smith ◽  
Gaëtan Herinckx ◽  
Nusrat Hussain ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Elongation Factor ◽  
Translation Elongation ◽  
Intact Cells ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
293 Cells ◽  
Eukaryotic Elongation Factor ◽  
A Site

eEF2K [eEF2 (eukaryotic elongation factor 2) kinase] phosphorylates and inactivates the translation elongation factor eEF2. eEF2K is not a member of the main eukaryotic protein kinase superfamily, but instead belongs to a small group of so-called α-kinases. The activity of eEF2K is normally dependent upon Ca2+ and calmodulin. eEF2K has previously been shown to undergo autophosphorylation, the stoichiometry of which suggested the existence of multiple sites. In the present study we have identified several autophosphorylation sites, including Thr348, Thr353, Ser366 and Ser445, all of which are highly conserved among vertebrate eEF2Ks. We also identified a number of other sites, including Ser78, a known site of phosphorylation, and others, some of which are less well conserved. None of the sites lies in the catalytic domain, but three affect eEF2K activity. Mutation of Ser78, Thr348 and Ser366 to a non-phosphorylatable alanine residue decreased eEF2K activity. Phosphorylation of Thr348 was detected by immunoblotting after transfecting wild-type eEF2K into HEK (human embryonic kidney)-293 cells, but not after transfection with a kinase-inactive construct, confirming that this is indeed a site of autophosphorylation. Thr348 appears to be constitutively autophosphorylated in vitro. Interestingly, other recent data suggest that the corresponding residue in other α-kinases is also autophosphorylated and contributes to the activation of these enzymes [Crawley, Gharaei, Ye, Yang, Raveh, London, Schueler-Furman, Jia and Cote (2011) J. Biol. Chem. 286, 2607–2616]. Ser366 phosphorylation was also detected in intact cells, but was still observed in the kinase-inactive construct, demonstrating that this site is phosphorylated not only autocatalytically but also in trans by other kinases.

De Novo Protein Synthesis Mediated by the Eukaryotic Elongation Factor 2 Is Required for the Anxiolytic Effect of Oxytocin

2019 ◽  
Vol 85 (10) ◽  
pp. 802-811 ◽  
Author(s):  
Stefanie Martinetz ◽  
Carl-Philipp Meinung ◽  
Benjamin Jurek ◽  
David von Schack ◽  
Erwin H. van den Burg ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
De Novo ◽  
Elongation Factor ◽  
Anxiolytic Effect ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
De Novo Protein Synthesis

Abstract 274: Expression and Phosphorylation States of Eukaryotic Elongation Factor 2 (EEF2) and EEF2 Kinase in Cardiomyocytes From Hypertrophy Models

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Satoshi Kameshima ◽  
Muneyoshi Okada ◽  
Shiro Ikeda ◽  
Yuki Watanabe ◽  
Hideyuki Yamawaki
Keyword(s):  
Protein Synthesis ◽  
Cardiac Hypertrophy ◽  
Elongation Factor ◽  
Protein Translation ◽  
Cardiomyocyte Hypertrophy ◽  
Specific Substrate ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Eef2 Kinase

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K, also known as calmodulin (CaM)-dependent protein kinase III) is regulated by both CaM-dependent and -independent mechanisms. Activated eEF2K phosphorylates and inactivates a specific substrate, eEF2. eEF2 activation facilitates protein translation. It is recognized that increased protein synthesis is one of the primary factors for cardiomyocyte hypertrophy. In fact, angiotensin II, which induces cardiomyocyte hypertrophy, was reported to facilitate eEF2 dephosphorylation (activation) and protein synthesis in rat isolated cardiomyocytes. We have previously demonstrated that protein expression of eEF2K was increased specifically in left ventricles (LV) of spontaneously hypertensive rats (SHR). However, expression and phosphorylation states of eEF2K and eEF2 in LV of other cardiac hypertrophy models are unknown. The aim of this study was to explore it. Male C57BL/6NJcl mice and Wistar rats received transverse aortic constriction (TAC) and isoproterenol (5 mg/kg; ISO) injection, respectively, which induced cardiac hypertrophy. After 3 and 28 days from TAC operation and 7 days from ISO injection, LV were isolated and used for Western blotting (WB) and immunohistochemistry (IHC). Echocardiography was done in TAC mice before LV isolation. In TAC-induced hypertrophied LV (3 days), eEF2K expression was significantly increased (p<0.01 vs. SHAM) and its phosphorylation at Ser366 was significantly decreased (p<0.05 vs. SHAM). Consistently, eEF2 phosphorylation was significantly increased (p<0.01 vs. SHAM). In LV from ISO rats, eEF2K phosphorylation at Ser366 was significantly decreased as determined by WB (p<0.01 vs. control). In addition, eEF2K- and phosphorylated eEF2-positive cardiomyocytes were increased as determined by IHC. These changes were also confirmed in LV from SHR. At 28 days after TAC, fractional shortening was significantly decreased (from 56.6±1.6% to 44.4±2.3%, p<0.01). Interestingly, eEF2 phosphorylation in LV was significantly decreased (p<0.05 vs. SHAM). The present results suggest the potential role of eEF2K/eEF2 signals in the pathogenesis of cardiac hypertrophy/failure.

The life and death of translation elongation factor 2

2006 ◽  
Vol 34 (1) ◽  
pp. 1-6 ◽  
Author(s):  
R. Jørgensen ◽  
A.R. Merrill ◽  
G.R. Andersen
Keyword(s):  
Functional Properties ◽  
Elongation Factor ◽  
Translation Elongation ◽  
Life And Death ◽  
Peptidyl Transfer ◽  
Structural Framework ◽  
Elongation Factor 2 ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Structural And Functional Properties

eEF2 (eukaryotic elongation factor 2) occupies an essential role in protein synthesis where it catalyses the translocation of the two tRNAs and the mRNA after peptidyl transfer on the 80 S ribosome. Recent crystal structures of eEF2 and the cryo-electron microscopy reconstruction of its 80 S complex now provide a substantial structural framework for dissecting the functional properties of this factor. The factor can be modified by either phosphorylation or ADP-ribosylation, which results in cessation of translation. We review the structural and functional properties of eEF2 with particular emphasis on the unique diphthamide residue, which is ADP-ribosylated by diphtheria toxin from Corynebacterium diphtheriae and exotoxin A from Pseudomonas aeruginosa.

A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy

2007 ◽  
Vol 292 (2) ◽  
pp. F617-F627 ◽  
Author(s):  
Myung-Ja Lee ◽  
Denis Feliers ◽  
Meenalakshmi M. Mariappan ◽  
Kavithalakshmi Sataranatarajan ◽  
Lenin Mahimainathan ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
High Glucose ◽  
Elongation Factor ◽  
Renal Hypertrophy ◽  
Elongation Factor 2 ◽  
Ampk Phosphorylation ◽  
Eukaryotic Elongation Factor 2 ◽  
Eukaryotic Elongation Factor ◽  
Induced Changes ◽  
Amp Activated Protein Kinase

We tested the hypothesis that AMP-activated protein kinase (AMPK), an energy sensor, regulates diabetes-induced renal hypertrophy. In kidney glomerular epithelial cells, high glucose (30 mM), but not equimolar mannitol, stimulated de novo protein synthesis and induced hypertrophy in association with increased phosphorylation of eukaryotic initiation factor 4E binding protein 1 and decreased phosphorylation of eukaryotic elongation factor 2, regulatory events in mRNA translation. These high-glucose-induced changes in protein synthesis were phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin (mTOR) dependent and transforming growth factor-β independent. High glucose reduced AMPK α-subunit theronine (Thr) 172 phosphorylation, which required Akt activation. Changes in AMP and ATP content could not fully account for high-glucose-induced reductions in AMPK phosphorylation. Metformin and 5-aminoimidazole-4-carboxamide-1β-riboside (AICAR) increased AMPK phosphorylation, inhibited high-glucose stimulation of protein synthesis, and prevented high-glucose-induced changes in phosphorylation of 4E binding protein 1 and eukaryotic elongation factor 2. Expression of kinase-inactive AMPK further increased high-glucose-induced protein synthesis. Renal hypertrophy in rats with Type 1 diabetes was associated with reduction in AMPK phosphorylation and increased mTOR activity. In diabetic rats, metformin and AICAR increased renal AMPK phosphorylation, reversed mTOR activation, and inhibited renal hypertrophy, without affecting hyperglycemia. AMPK is a newly identified regulator of renal hypertrophy in diabetes.

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