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Arrestin regulates MAPK activation and prevents NADPH oxidase-dependent death of cells expressing CXCR2.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2004 Nov 19; Vol. 279 (47), pp. 49259-67. Date of Electronic Publication: 2004 Sep 13. - Publication Year :
- 2004
-
Abstract
- Activation of CXCR2 IL-8 receptor leads to activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and rapid receptor endocytosis. Co-immunoprecipitation and co-localization experiments showed that arrestin and CXCR2 form complexes with components of the ERK1/2 cascade following ligand stimulation. However, in contrast to the activation of the beta2-adrenergic receptor, arrestin was not necessary for ERK1/2 phosphorylation or receptor endocytosis. In contrast, beta-arrestin 1/2 double knockout cells showed greatly enhanced phosphorylation of ERK1/2, as well as phosphorylation of the stress kinases p38 and c-Jun N-terminal protein kinase. The stimulation of stress kinases in arrestin double knockout cells could be attenuated in the presence of diphenylene iodonium (DPI), an inhibitor of the NADPH oxidase, suggesting that reactive oxidant species (ROS) participated in mitogen-activated protein kinase (MAPK) activation. ROS could indeed be detected in IL-8-stimulated beta-arrestin 1/2 knockout cells, and cytoplasmic Rac was translocated to the membrane fraction, which is a prerequisite for oxidant formation. The oxidative burst induced cell death within 6 h of IL-8 stimulation of these cells, which could be prevented in the presence of DPI. These results indicate a novel function for arrestin, which is protection from an excessive oxidative burst, resulting from the sustained stimulation of G-protein-coupled receptors that cause Rac translocation.
- Subjects :
- Animals
Cell Death
Cell Line
Cell Membrane metabolism
Chemokine CXCL12
Chemokines, CXC metabolism
Cytoplasm metabolism
Endocytosis
Enzyme Inhibitors pharmacology
Escherichia coli metabolism
Genes, Dominant
Humans
Immunoblotting
Immunoprecipitation
Interleukin-8 metabolism
JNK Mitogen-Activated Protein Kinases metabolism
Mice
Microscopy, Fluorescence
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Onium Compounds pharmacology
Oxidants metabolism
Oxidative Stress
Phosphorylation
Plasmids metabolism
Protein Binding
Protein Transport
Proto-Oncogene Proteins c-raf metabolism
Reactive Oxygen Species
Respiratory Burst
Subcellular Fractions
Time Factors
Transfection
beta-Arrestin 1
beta-Arrestins
p38 Mitogen-Activated Protein Kinases metabolism
Arrestins physiology
MAP Kinase Signaling System
NADPH Oxidases metabolism
Receptors, Interleukin-8B physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 279
- Issue :
- 47
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15364949
- Full Text :
- https://doi.org/10.1074/jbc.M405118200