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J. Biol. Chem., Vol. 279, Issue 46, 48255-48261, November 12, 2004

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Stable Interaction between -Arrestin 2 and Angiotensin Type 1A Receptor Is Required for -Arrestin 2-mediated Activation of Extracellular Signal-regulated Kinases 1 and 2^*

Huijun Wei, Seungkirl Ahn, William G. Barnes, and Robert J. Lefkowitz, Investigator of the Howard Hughes Medical Institute

From the Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710

Binding of -arrestins to seven-membrane-spanning receptors (7MSRs) not only leads to receptor desensitization and endocytosis but also elicits additional signaling processes. We recently proposed that stimulation of the angiotensin type 1A (AT_1A) receptor results in independent -arrestin 2- and G protein-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation. Here we utilize two AT_1A mutant receptors to study these independent pathways, one truncated at residue 324, thus removing all potential carboxyl-terminal phosphorylation sites, and the other bearing four mutations in the serine/threonine-rich clusters in the carboxyl terminus. As assessed by confocal microscopy, the two mutant receptors interacted with -arrestin 2-green fluorescent protein with much lower affinity than did the wild-type receptor. In addition, the mutant receptors more robustly stimulated G protein-mediated inositol phosphate production. Approximately one-half of the wild-type AT_1A receptor-stimulated ERK1/2 activation was via a -arrestin 2-dependent pathway (suppressed by -arrestin 2 small interfering RNA), whereas the rest was mediated by a G protein-dependent pathway (suppressed by protein kinase C inhibitor). ERK1/2 activation by the mutant receptors was insensitive to -arrestin 2 small interfering RNA but was reduced more than 80% by a protein kinase C inhibitor. The biochemical consequences of ERK activation by the G protein and -arrestin 2-dependent pathways were also distinct. G-protein-mediated ERK activation enhanced the transcription of early growth response 1, whereas -arrestin 2-dependent ERK activation did not. In addition, stimulation of the truncated AT_1A mutant receptor caused significantly greater early growth response 1 transcription than did the wild-type receptor. These findings demonstrate how the ability of receptors to interact with -arrestins determines both the mechanism of ERK activation as well as the physiological consequences of this activation.

Received for publication, June 3, 2004 , and in revised form, August 30, 2004.

^* This work was supported by National Institutes of Health Grants RO1 HL16037 and HL70631 (to R. J. L.). 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: Howard Hughes Medical Inst., Depts. of Medicine and Biochemistry, Box 3821, Duke University Medical Ctr., Durham, NC 27710. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001{at}receptor-biol.duke.edu.

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