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J. Biol. Chem., Vol. 281, Issue 28, 19346-19357, July 14, 2006
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-Arrestin1 Fusion Protein
1
From the
Departments of Medicine, Biochemistry & Molecular Biology, and Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425 and The Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401
The 
-arrestins, a small family of G protein-coupled receptor (GPCR)-binding proteins involved in receptor desensitization, have been shown to bind extracellular signal-regulated kinases 1 and 2 (ERK1/2) and function as scaffolds for GPCR-stimulated ERK1/2 activation. To better understand the mechanism of -arrestin-mediated ERK1/2 activation, we compared ERK1/2 activation by the wild-type neurokinin 1 (NK1) receptor with a chimeric NK1 receptor having -arrestin1 fused to the receptor C terminus (NK1-Arr1). The NK1 receptor couples to both Gs and Gq/11, resides on the plasma membrane, and mediates rapid ERK1/2 activation and nuclear translocation in response to neurokinin A. In contrast, NK1-Arr1 is a G protein-uncoupled "constitutively desensitized" receptor that resides almost entirely in an intracellular endosomal compartment. Despite its inability to respond to neurokinin A, we found that NK1-Arr1 expression caused robust constitutive activation of cytosolic ERK1/2 and that endogenous Raf, MEK1/2, and ERK1/2 coprecipitated in a complex with NK1-Arr1. While agonist-dependent ERK1/2 activation by the NK1 receptor was independent of protein kinase A (PKA) or PKC activity, NK1-Arr1-mediated ERK1/2 activation was completely inhibited when basal PKA and PKC activity were blocked. In addition, the rate of ERK1/2 dephosphorylation was slowed in NK1-Arr1-expressing cells, suggesting that -arrestin-bound ERK1/2 is protected from mitogen-activated protein kinase phosphatase activity. These data suggest that -arrestin binding to GPCRs nucleates the formation of a stable "signalsome" that functions as a passive scaffold for the ERK1/2 cascade while confining ERK1/2 activity to an extranuclear compartment.
Received for publication, November 28, 2005 , and in revised form, April 26, 2006.
* This work was supported by National Institutes of Health Grant DK55524 (to L. M. L.), the South Carolina Center for Biomedical Research Excellence in Cardiovascular Diseases (to D. K. L.), and the Department of Veterans Affairs. 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: Division of Endocrinology, Diabetes and Medical Genetics, Dept. of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St., 816 CSB, P. O. Box 250624, Charleston, SC 29425. Tel.: 843-792-2529; Fax: 843-792-4114; E-mail: luttrell{at}musc.edu.
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