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J. Biol. Chem., Vol. 284, Issue 1, 685-695, January 2, 2009

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How Does Arrestin Assemble MAPKs into a Signaling Complex?^*

Xiufeng Song, Sergio Coffa, Haian Fu, and Vsevolod V. Gurevich¹

From the Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232 and the Department of Pharmacology, Emory University, Atlanta, Georgia 30322

Arrestins bind active phosphorylated G protein-coupled receptors, precluding G protein activation and channeling signaling to alternative pathways. Arrestins also function as mitogen-activated protein kinase (MAPK) scaffolds, bringing together three components of MAPK signaling modules. Here we have demonstrated that all four vertebrate arrestins interact with JNK3, MKK4, and ASK1, but only arrestin3 facilitates JNK3 activation. Thus, the functional specificity of arrestins is not determined by differential binding of the kinases. Using receptor binding-impaired mutant, we have shown that free arrestin3 readily promotes JNK3 phosphorylation. We identified key arrestin-binding elements in JNK3 and ASK1 and investigated the molecular interactions of arrestin2 and arrestin3 and their individual domains with the components of the two MAPK cascades, ASK1-MKK4-JNK3 and c-Raf-1-MEK1-ERK2. We found that both arrestin domains interact with all six kinases. These findings shed new light on the mechanism of arrestin-mediated MAPK activation and the spatial arrangement of the three kinases on arrestin molecule.

Received for publication, August 7, 2008 , and in revised form, November 6, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM077561, GM081756, and EY011500 (to V. V. G.). 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.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Vanderbilt University, 2200 Pierce Ave., PRB, Rm. 418, Nashville, TN 37232. Tel.: 615-322-7070; Fax: 615-343-6532; E-mail: vsevolod.gurevich{at}vanderbilt.edu.

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