A kinase inhibitor activates the IRE1α RNase to confer cytoprotection against ER stress
| Autor: | Joseph A. Callahan, Scott A. Oakes, Feroz R. Papa, Dan Han, Andrew Hagen, John-Paul Upton |
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| Rok vydání: | 2008 |
| Předmět: |
Biophysics
Protein Serine-Threonine Kinases Mitogen-activated protein kinase kinase Endoplasmic Reticulum Biochemistry MAP2K7 Mice TANK-binding kinase 1 Endoribonucleases Animals ASK1 Protein Kinase Inhibitors Molecular Biology Cells Cultured Dose-Response Relationship Drug biology MAP kinase kinase kinase Cyclin-dependent kinase 4 Cyclin-dependent kinase 2 Cell Biology Fibroblasts Molecular biology Enzyme Activation Oxidative Stress Cytoprotection biology.protein Cyclin-dependent kinase 9 |
| Zdroj: | Biochemical and Biophysical Research Communications. 365:777-783 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2007.11.040 |
| Popis: | Unfolded proteins in the endoplasmic reticulum (ER) cause trans-autophosphorylation of the bifunctional transmembrane kinase IRE1alpha, inducing its RNase activity to splice XBP1 mRNA, in turn triggering a transcriptional program in the unfolded protein response (UPR). As we previously showed with the yeast IRE1 kinase ortholog, a single missense mutation in the ATP-binding pocket of murine IRE1alpha kinase sensitizes it to the ATP-competitive inhibitor 1NM-PP1, and subordinates RNase activity to the drug. This highly unusual mechanism of kinase signaling requiring kinase domain ligand occupancy-even through an inhibitor-to activate a nearby RNase has therefore been completely conserved through evolution. We also demonstrate that engagement of the drug-sensitized IRE1alpha kinase through this maneuver affords murine cells cytoprotection under ER stress. Thus kinase inhibitors of IRE1alpha are useful for altering the apoptotic outcome to ER stress, and could possibly be developed into drugs to treat ER stress-related diseases. |
| Databáze: | OpenAIRE |
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