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J. Biol. Chem., Vol. 279, Issue 47, 49259-49267, November 19, 2004

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Arrestin Regulates MAPK Activation and Prevents NADPH Oxidase-dependent Death of Cells Expressing CXCR2^*

Ming Zhao, Antonia Wimmer, Khanh Trieu, Richard G. DiScipio, and Ingrid U. Schraufstatter

From the Division of Cancer Biology, La Jolla Institute for Molecular Medicine, San Diego, California 92121

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 ₂-adrenergic receptor, arrestin was not necessary for ERK1/2 phosphorylation or receptor endocytosis. In contrast, -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 -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.

Received for publication, May 7, 2004 , and in revised form, September 9, 2004.

^* This work was funded by National Institutes of Health Grant HL55657 (to I. U. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: La Jolla Institute for Molecular Medicine, 4570 Executive Dr., 100, San Diego, CA 92121. Tel.: 858-587-8788, ext. 131; Fax: 858-587-6742; E-mail: mzhao{at}ljimm.org.

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