Mitochondrial signals initiate the activation of c‐JunN‐terminal kinase (JNK) by hypoxia‐reoxygenation
| Autor: | Lori A. Kubasiak, Christopher J. Dougherty, Nanette H. Bishopric, Donna P. Frazier, Keith A. Webster, Wen Cheng Xiong, Huifang Li |
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| Rok vydání: | 2004 |
| Předmět: |
rac1 GTP-Binding Protein
MAPK/ERK pathway MAP Kinase Signaling System Antimycin A Apoptosis Biology Biochemistry Proinflammatory cytokine Electron Transport Oxygen Consumption Calcium flux Genetics Animals Myocytes Cardiac Calcium Signaling Phosphorylation cdc42 GTP-Binding Protein Protein kinase A Molecular Biology Cells Cultured MAP kinase kinase kinase Kinase c-jun JNK Mitogen-Activated Protein Kinases Hydrogen Peroxide Protein-Tyrosine Kinases Cell Hypoxia Mitochondria Rats Cell biology Enzyme Activation Focal Adhesion Kinase 2 Signal transduction Reactive Oxygen Species Protein Processing Post-Translational Anisomycin Signal Transduction Biotechnology |
| Zdroj: | The FASEB Journal. 18:1060-1070 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.04-1505com |
| Popis: | C-Jun N-terminal kinase (JNK) is part of the mitogen-activated protein kinase (MAPK) family of signaling pathways that are induced in response to extracellular stimuli. JNK is primarily a stress-response pathway and can be activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through non-receptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). The molecular initiators of MAPKs by non-receptor stimuli have not been described. Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We show here that the activation of JNK by this condition is initiated in the mitochondria and requires coupled electron transport, ROI generation, and calcium flux. These signals cause the selective, sequential activation of the calcium-dependent, proline-rich kinase Pyk2 and the small GTP binding factors Rac-1 and Cdc42. Interruption of these interactions with inactivated dominant negative mutant proteins, blocking calcium flux, or inhibiting electron transport through mitochondrial complexes II, III, or IV prevents JNK activation and results in a proapoptotic phenotype that is characteristic of JNK inhibition in this model of ischemia-reperfusion. The signaling pathway is unique for the reoxygenation stimulus and provides a framework for other non-receptor-mediated pathways of MAPK activation. |
| Databáze: | OpenAIRE |
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