Ca<sup>2+</sup>/calmodulin‐dependent phosphorylation of elongation factor 2

Ryazanov, Alexey G.

doi:10.1016/0014-5793(87)80081-9

Cited by 143 publications

(93 citation statements)

References 13 publications

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“…Furthermore, pharmacological inducers of ER stress such as Tm and thapsigargin (Tg), an inhibitor of the ER-resident Ca 2 þ -dependent ATPase, induced eEF-2 phosphorylation with kinetics similar to those of sal (Supplementary Figure 3). EEF-2 phosphorylation has been observed in response to several stimuli, [26][27][28][29][30][31][32][33] but never in the context of ER stress. Our observations suggest that eEF-2 might be regulated by phosphorylation during ESR.…”

Section: Resultsmentioning

confidence: 99%

“…One attractive candidate for this mechanism is calcium flux into the cytoplasm, which occurs during some types of ER stress 5,11,59,60 and is known to promote eEF-2K activation. 26 Importantly, however, Tm induces relatively little calcium flux in most cell types, including PC12, used in our system. 61 Indeed, we relied primarily on Tm in our experiments, to induce robust ER stress while minimizing calcium flux, enabling us to discriminate between the phenotypic effects of ER dysfunction per se and the more pleiotropic downstream effects of calcium flux.…”

Section: Discussionmentioning

confidence: 95%

“…[22][23][24] The phosphorylation of eEF-2 is catalyzed by eEF-2 kinase (eEF-2K), an unusual calcium/calmodulin-dependent enzyme belonging to the alpha kinase family of atypical protein kinases. 25 EEF-2 phosphorylation has been shown to play an important role in coupling protein synthesis to energy metabolism in response to calcium flux, 26 cyclic adenosine monophosphate (AMP)/protein kinase A and AMP-activated protein kinase signaling, [27][28][29][30] amino acid or glucose limitation, 31,32 and cytoplasmic pH changes, 33 but no role for eEF-2 phosphorylation in ER stress has been reported.…”

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confidence: 99%

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A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

Boyce

Ryazanov

et al. 2008

Cell Death Differ

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Apoptosis triggered by endoplasmic reticulum (ER) stress has been implicated in many diseases but its cellular regulation remains poorly understood. Previously, we identified salubrinal (sal), a small molecule that protects cells from ER stressinduced apoptosis by selectively activating a subset of endogenous ER stress-signaling events. Here, we use sal as a probe in a proteomic approach to discover new information about the endogenous cellular response to ER stress. We show that sal induces phosphorylation of the translation elongation factor eukaryotic translation elongation factor 2 (eEF-2), an event that depends on eEF-2 kinase (eEF-2K). ER stress itself also induces eEF-2K-dependent eEF-2 phosphorylation, and this pathway promotes translational arrest and cell death in this context, identifying eEF-2K as a hitherto unknown regulator of ER stress-induced apoptosis. Finally, we use both sal and ER stress models to show that eEF-2 phosphorylation can be activated by at least two signaling mechanisms. Our work identifies eEF-2K as a new component of the ER stress response and underlines the utility of novel small molecules in discovering new cell biology. Cell Death and Differentiation (2008) 15, 589-599; doi:10.1038/sj.cdd.4402296; published online 11 January 2008 The endoplasmic reticulum (ER) serves as the primary processing site for membrane and secreted proteins. The ER recruits translating ribosomes, translocates newly synthesized polypeptides into its lumen, and promotes a variety of post-translational modifications and chaperone-facilitated protein folding. 1,2 Proper ER function is critical for numerous aspects of cell physiology, including vesicle trafficking, lipid and membrane biogenesis, and protein targeting and secretion. Accordingly, cells react rapidly to various forms of ER dysfunction -including the accumulation of unfolded, misfolded or excessive protein, ER lipid or glycolipid imbalances, or changes in the redox or ionic conditions of the ER lumenthrough a set of adaptive pathways known collectively as the ER stress response (ESR). [2][3][4][5] The ESR promotes cell survival both by increasing the capacity of the ER to fold and process client proteins and by reducing the amount of protein inside the ER. These effects are achieved through three major pathways: (1) the unfolded protein response, a transcription-dependent induction of ER lumenal chaperone proteins and many other components of the secretory apparatus, which augments the polypeptide processing capacity of the ER; 5,6 (2) the activation of proteasome-dependent ER-associated degradation to remove proteins from the ER; 7,8 and (3) the control of protein translation to modulate the polypeptide traffic into the ER. 9,10 Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger apoptosis. [11][12][13][14] ER stress and the apoptotic program coupled to it have been implicated in many important pathologies, including diabetes, obesity, neurodegenerativ...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 99%

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A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

Boyce

Ryazanov

et al. 2008

Cell Death Differ

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“…6 is a ubiquitously expressed eukaryotic calcium/calmodulin (Ca 2ϩ /CaM)-regulated protein kinase (1)(2)(3)(4), which lacks sequence homology with typical protein kinases. It is therefore classified as an atypical kinase, belonging to the same family as myosin II heavy chain kinase (MHCK A) (5,6).…”

Section: Eef-2kmentioning

confidence: 99%

The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation

Tavares¹,

Ferguson

Giles

et al. 2014

Journal of Biological Chemistry

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Background: Eukaryotic elongation factor 2 kinase (eEF-2K) regulates protein translation elongation rates. Results: eEF-2K activation involves a two-step process of calmodulin binding and rapid Thr-348 autophosphorylation. Conclusion: Activation of eEF-2K involves two distinct allosteric steps, both of which potentially induce a conformational change. Significance: This mechanism provides a framework for understanding how eEF-2K integrates inputs from multiple upstream signaling pathways.

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“…Phosphorylation of eEF-2 is catalysed by a Ca" and calmodulin-dependent protein kinase CaM PK III [5,6] while reactivation by dephosphorylation is mainly dependent on phosphoprotein phosphatase 2A [7,8]. The activity of the CaM PK III is dependent on the phosphorylation status of the enzyme and the dephosphorylated kinase shows no catalytic activity [9-l 11.…”

Section: Introductionmentioning

confidence: 99%

Interaction of the calcium and calmodulin regulated eEF‐2 kinase with heat shock protein 90

et al. 1994

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Immunoadsorbents containing the 8D3 anti-heat shock protein 90 monoclonal antibodies were prepared. Partly purified preparations of the Ca'+ and calmodulin dependent eukaryotic elongation factor eEF-2 specific kinase and crude rabbit reticulocyte lysates were mixed with the immunoadsorbent. After removal of unbound proteins the adsorbed material was released by increasing the salt concentration in the buffer. Analysis of the bound material showed that the eEF-2 kinase was bound to the immunoadsorbent together with hsp 90. The adsorption of the kinase was found to depend on the presence of hsp 90.

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Ca²⁺/calmodulin‐dependent phosphorylation of elongation factor 2

Cited by 143 publications

References 13 publications

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation

Interaction of the calcium and calmodulin regulated eEF‐2 kinase with heat shock protein 90

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Ca2+/calmodulin‐dependent phosphorylation of elongation factor 2

Cited by 143 publications

References 13 publications

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation

Interaction of the calcium and calmodulin regulated eEF‐2 kinase with heat shock protein 90

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Ca²⁺/calmodulin‐dependent phosphorylation of elongation factor 2