cJun N-terminal kinase (JNK) phosphorylation of serine 36 is critical for p66Shc activation
| Autor: | Sana, Khalid, Astrid, Drasche, Marco, Thurner, Martin, Hermann, Muhammad Imtiaz, Ashraf, Friedrich, Fresser, Gottfried, Baier, Leopold, Kremser, Herbert, Lindner, Jakob, Troppmair |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Src Homology 2 Domain-Containing
Transforming Protein 1 Cell Death JNK Mitogen-Activated Protein Kinases Oxidants environment and public health Cell Hypoxia Recombinant Proteins Article Mitochondria Enzyme Activation Oxygen enzymes and coenzymes (carbohydrates) Gene Knockout Techniques Mice Oxidative Stress Phosphoserine Phenotype Protein Kinase C beta Animals Mutant Proteins Phosphorylation Reactive Oxygen Species Protein Kinase Inhibitors DNA Damage Protein Binding |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep20930 |
| Popis: | p66Shc-dependent ROS production contributes to many pathologies including ischemia/reperfusion injury (IRI) during solid organ transplantation. Inhibiting p66Shc activation may provide a novel therapeutic approach to prevent damage, which is poorly managed by antioxidants in vivo. Previous work suggested that pro-oxidant and a pro-apoptotic function of p66Shc required mitochondrial import, which depended on serine 36 phosphorylation. PKCß has been proposed as S36 kinase but cJun N-terminal kinases (JNKs) may also phosphorylate this residue. To simulate the early stages of ischemia/reperfusion (IR) we either used H2O2 treatment or hypoxia/reoxygenation (HR). As during reperfusion in vivo, we observed increased JNK and p38 activity in mouse embryonic fibroblasts (MEFs) and HL-1 cardiomyocytes along with significantly increased p66ShcS36 phosphorylation, ROS production and cell damage. Application of specific inhibitors caused a pronounced decrease in p66ShcS36 phosphorylation only in the case of JNK1/2. Moreover, S36 phosphorylation of recombinant p66Shc by JNK1 but not PKCß was demonstrated. We further confirmed JNK1/2-dependent regulation of p66ShcS36 phosphorylation, ROS production and cell death using JNK1/2 deficient MEFs. Finally, the low ROS phenotype of JNK1/2 knockout MEFs was reversed by the phosphomimetic p66ShcS36E mutant. Inhibiting JNK1/2-regulated p66Shc activation may thus provide a therapeutic approach for the prevention of oxidative damage. |
| Databáze: | OpenAIRE |
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