cAMP-dependent activation of protein synthesis correlates with dephosphorylation of elongation factor 2

FEBS Letters ◽  
1988 ◽  
Vol 228 (2) ◽  
pp. 327-331 ◽  
Author(s):  
A.S. Sitikov ◽  
P.N. Simonenko ◽  
E.A. Shestakova ◽  
A.G. Ryazanov ◽  
L.P. Ovchinnikov
Keyword(s):  
Protein Synthesis ◽  
Elongation Factor ◽  
Elongation Factor 2

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.

scholarly journals Translation elongation factor 2 depletion by siRNA in mouse liver leads to mTOR-independent translational upregulation of ribosomal protein genes

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Maxim V. Gerashchenko ◽  
Mikhail V. Nesterchuk ◽  
Elena M. Smekalova ◽  
Joao A. Paulo ◽  
Piotr S. Kowalski ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mammalian Cells ◽  
Ribosomal Proteins ◽  
Mouse Liver ◽  
Negative Impact ◽  
Elongation Factor ◽  
Ribosome Profiling ◽  
Translation Elongation Factor ◽  
Translation Elongation ◽  
Elongation Factor 2

Abstract Due to breakthroughs in RNAi and genome editing methods in the past decade, it is now easier than ever to study fine details of protein synthesis in animal models. However, most of our understanding of translation comes from unicellular organisms and cultured mammalian cells. In this study, we demonstrate the feasibility of perturbing protein synthesis in a mouse liver by targeting translation elongation factor 2 (eEF2) with RNAi. We were able to achieve over 90% knockdown efficacy and maintain it for 2 weeks effectively slowing down the rate of translation elongation. As the total protein yield declined, both proteomics and ribosome profiling assays showed robust translational upregulation of ribosomal proteins relative to other proteins. Although all these genes bear the TOP regulatory motif, the branch of the mTOR pathway responsible for translation regulation was not activated. Paradoxically, coordinated translational upregulation of ribosomal proteins only occurred in the liver but not in murine cell culture. Thus, the upregulation of ribosomal transcripts likely occurred via passive mTOR-independent mechanisms. Impaired elongation sequesters ribosomes on mRNA and creates a shortage of free ribosomes. This leads to preferential translation of transcripts with high initiation rates such as ribosomal proteins. Furthermore, severe eEF2 shortage reduces the negative impact of positively charged amino acids frequent in ribosomal proteins on ribosome progression.

Angiotensin II regulates phosphorylation of translation elongation factor-2 in cardiac myocytes

2001 ◽  
Vol 281 (1) ◽  
pp. H161-H167 ◽  
Author(s):  
Allen D. Everett ◽  
Tamara D. Stoops ◽  
Angus C. Nairn ◽  
David Brautigan
Keyword(s):  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Cardiac Myocytes ◽  
Elongation Factor ◽  
Protein Translation ◽  
Mitogen Activated Protein Kinase ◽  
Ang Ii ◽  
Elongation Factor 2 ◽  
Mitogen Activated Protein ◽  
20 Nm

Increased protein synthesis is the cardinal feature of cardiac hypertrophy. We have studied angiotensin II (ANG II)-dependent regulation of eukaryotic elongation factor-2 (eEF-2), an essential component of protein translation required for polypeptide elongation, in rat neonatal cardiac myocytes. eEF2 is fully active in its dephosphorylated state and is inhibited following phosphorylation by eEF2 kinase. ANG II treatment (10−10–10−7 M) for 30 min produced an AT1 receptor-specific and concentration- and time-dependent reduction in the phosphorylation of eEF-2. Protein phosphatase 2A (PP2A) inhibitors okadaic acid and fostriecin, but not the PP2B inhibitor FK506, attenuated ANG II-dependent dephosphorylation of eEF-2. ANG II activated mitogen-activated protein kinase, (MAPK) within 10 min of treatment, and blockade of MAPK activation with PD-98059 (1–20 nM) inhibited eEF-2 dephosphorylation. The effect of ANG II on eEF-2 dephosphorylation was also blocked by LY-29004 (1–20 nM), suggesting a role for phosphoinositide 3-kinase, but the mammalian target rapamycin inhibitor rapamycin (10–100 nM) had no effect. Together these results suggest that the ANG II-dependent increase in protein synthesis includes activation of eEF-2 via dephosphorylation by PP2A by a process that involves both PI3K and MAPK.

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.

Eukaryotic elongation factor-2 (eEF-2) activity in bovine mammary tissue in relation to milk protein synthesis

2002 ◽  
Vol 69 (2) ◽  
pp. 205-212 ◽  
Author(s):  
CLAUS T. CHRISTOPHERSEN ◽  
JAKOB KARLSEN ◽  
METTE O. NIELSEN ◽  
BENT RIIS
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Mammary Gland ◽  
Diphtheria Toxin ◽  
Milk Protein ◽  
Elongation Factor ◽  
Mammary Tissue ◽  
Limiting Factor ◽  
Elongation Factor 2 ◽  
High Level

The amount of protein synthesis translational elongation factor 2 (eEF-2) was estimated employing diphtheria toxin-dependent ADP-ribosylation in samples prepared from small amounts of tissue from mammary gland, skeletal muscle and liver from lactating dairy cows. A very high level of ADP-ribosylatable eEF-2 was found in mammary gland, amounting to 20-times the level found in liver and 50-times the level found in skeletal muscle. This obviously reflects the high protein synthesis activity in mammary tissue. To our knowledge, similar high activities have previously been reported only for cancer cells. A close linear relationship was found between the amount of diphtheria-toxin catalysed ADP-ribosylated eEF-2 and protein and casein output in milk from cows in late lactation. This strongly suggests that eEF-2 may be a limiting factor in milk protein synthesis.

scholarly journals The mode of action of Shiga toxin on peptide elongation of eukaryotic protein synthesis

1987 ◽  
Vol 244 (2) ◽  
pp. 287-294 ◽  
Author(s):  
T G Obrig ◽  
T P Moran ◽  
J E Brown
Keyword(s):  
Protein Synthesis ◽  
Complex Formation ◽  
Shiga Toxin ◽  
Mode Of Action ◽  
Elongation Factor ◽  
Shigella Dysenteriae ◽  
Gtpase Activity ◽  
Elongation Factor 2 ◽  
Peptide Elongation ◽  
Elongation Factor 1

The effect of Shiga toxin, from Shigella dysenteriae 1, on the component reactions of peptide elongation were investigated. Enzymic binding of [3H]phenylalanine-tRNA to reticulocyte ribosomes was inhibited by 50% at 7 nM toxin. Elongation factor 1 (eEF-1)-dependent GTPase activity was also inhibited. Both reactions were not restored by addition of excess eEF-1 protein. In contrast, toxin concentrations of 200 nM were required to inhibit by 50% the elongation factor 2 (eEF-2)-dependent translocation of aminoacyl-tRNA on ribosomes. Addition of excess eEF-2 restored translocation activity. The eEF-2-dependent GTPase activity was unaffected at toxin concentrations below 100 nM, and Shiga-toxin concentrations of up to 1,000 nM did not affect either GTP.eEF-2.ribosome complex-formation or peptidyltransferase activity. Thus Shiga toxin closely resembles alpha-sarcin in action, both being primary inhibitors of eEF-1-dependent reactions. In contrast, the 60 S ribosome inactivators ricin and phytolaccin are primary inhibitors of eEF-2-dependent reactions of peptide elongation.

scholarly journals Inhibition by ricin of protein synthesis in vitro. Inhibition of the binding of elongation factor 2 and of adenosine diphosphate-ribosylated elongation factor 2 to ribosomes

1975 ◽  
Vol 146 (1) ◽  
pp. 127-131 ◽  
Author(s):  
L Montanaro ◽  
S Sperti ◽  
A Mattioli ◽  
G Testoni ◽  
F Stirpe
Keyword(s):  
Protein Synthesis ◽  
Binding Sites ◽  
Polypeptide Chain ◽  
Elongation Factor ◽  
Adenosine Diphosphate ◽  
Chain Elongation ◽  
Elongation Factor 2 ◽  
In Vitro Inhibition ◽  
Liver Ribosomes

The binding of EF2 (elongation factor 2) and of ADP-ribosyl-EF 2 to rat liver ribosomes is inhibited by ricin. This result suggests that the native enzyme and its ADP-ribose derivative have the same or closely related binding sites on the ribosome. The inhibition by ricin of the binding of EF 2 to ribosomes is consistent with the previous observation that ricin affects EF 2-catalysed translocation during polypeptide chain elongation.

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