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J. Biol. Chem., Vol. 281, Issue 52, 39796-39805, December 29, 2006

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G Protein-coupled Receptor (GPCR) Kinase 2 Regulates Agonist-independent G_q/11 Signaling from the Mouse Cytomegalovirus GPCR M33^*

From the Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524

The mouse cytomegalovirus M33 protein is highly homologous to mammalian G protein-coupled receptors (GPCRs) yet functions in an agonist-independent manner to activate a number of classical GPCR signal transduction pathways. M33 is functionally similar to the human cytomegalovirus-encoded US28 GPCR in its ability to induce inositol phosphate accumulation, activate NF-B, and promote smooth muscle cell migration. This ability to promote cellular migration suggests a role for viral GPCRs like M33 in viral dissemination in vivo, and accordingly, M33 is required for efficient murine cytomegalovirus replication in the mouse. Although previous studies have identified several M33-induced signaling pathways, little is known regarding the membrane-proximal events involved in signaling and regulation of this receptor. In this study, we used recombinant retroviruses to express M33 in wild-type and G_q/11^–/– mouse embryonic fibroblasts and show that M33 couples directly to the G_q/11 signaling pathway to induce high levels of total inositol phosphates in an agonist-independent manner. Our data also show that GRK2 is a potent regulator of M33-induced G_q/11 signaling through its ability to phosphorylate M33 and sequester G_q/11 proteins. Taken together, the results from this study provide the first genetic evidence of a viral GPCR coupling to a specific G protein signaling pathway as well as identify the first viral GPCR to be regulated specifically by both the catalytic activity of the GRK2 kinase domain and the G_q/11 binding activity of the GRK2 RH domain.

Received for publication, October 25, 2006

^* This work was supported by National Institutes of Health Grant R01 AI058159 and March of Dimes Grant 5-FY-04-17. 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 Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0524. Tel.: 513-558-0866; Fax: 513-558-8474; E-mail: william.miller{at}uc.edu.

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