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lüll A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death Boyce M; Py BF; Ryazanov AG; Minden JS; Long K; Ma D; Yuan JCell Death Differ 2008[Mar]; 15 (3): 589-99Apoptosis 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 stress-induced 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.|*Apoptosis[MESH]|Animals[MESH]|Cells, Cultured[MESH]|Cinnamates/*pharmacology[MESH]|Elongation Factor 2 Kinase/*metabolism[MESH]|Endoplasmic Reticulum/*metabolism[MESH]|Eukaryotic Initiation Factor-2/metabolism[MESH]|Mice[MESH]|PC12 Cells[MESH]|Peptide Elongation Factor 2/*metabolism[MESH]|Proteomics[MESH]|Rats[MESH]|Signal Transduction[MESH]|Thiourea/*analogs & derivatives/pharmacology[MESH] |