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J. Biol. Chem., Vol. 281, Issue 24, 16757-16767, June 16, 2006

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Up-regulation of the Angiotensin II Type 1 Receptor by the MAS Proto-oncogene Is Due to Constitutive Activation of G_q/G₁₁ by MAS^*

From the Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom

Coexpression of the MAS proto-oncogene with the angiotensin II type 1 (AT₁) receptor in CHO-K1 cells has been reported to increase the number of [³H]angiotensin II-binding sites, although MAS does not bind [³H]angiotensin II. In HEK293 cells stably expressing AT₁ receptor-cyan fluorescent protein (CFP), MAS-yellow fluorescent protein (YFP) expression from an inducible locus caused strong up-regulation of AT₁ receptor-CFP amounts and [³H]angiotensin II binding levels. The time course of AT₁ receptor-CFP up-regulation was also markedly slower than that of induction of MAS expression. These effects were not mimicked by induced expression of I138D MAS-YFP, a mutant unable to cause constitutive loading of [³⁵S]guanosine 5'-O-(thiotriphosphate) onto the phospholipase C-linked G protein G₁₁. Protein kinase C (PKC) inhibitors and the selective G_q/G₁₁ inhibitor YM-254890 fully blocked MAS-induced up-regulation of AT₁ receptor-CFP amounts, whereas the PKC activator phorbol 12-myristate 13-acetate produced strong up-regulation of AT₁ receptor-CFP without induction of MAS-YFP expression and in the presence of I138D MAS-YFP. The C-terminal tail of the AT₁ receptor is a known target for PKC-mediated phosphorylation. In cells stably expressing a C-terminally truncated version of the AT receptor, induction of MAS expression did not up-regulate the truncated construct levels. These data demonstrate that the ability of MAS to up-regulate AT₁ receptor levels reflects the constitutive capacity of MAS to activate G_q/G₁₁ and hence stimulate PKC-dependent phosphorylation of the AT₁ receptor.

Received for publication, February 6, 2006 , and in revised form, April 10, 2006.

^* This work was supported by the Medical Research Council. 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: Div. of Biochemistry and Molecular Biology, University of Glasgow, Davidson Bldg., University Ave., Glasgow G12 8QQ, Scotland, UK. Tel.: 44-141-330-5557; Fax: 44-141-330-4620; E-mail: g.milligan{at}bio.gla.ac.uk.

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