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 G 11. Protein kinase C (PKC) inhibitors and the selective G q/G 11 inhibitor YM-254890 fully blocked MAS-induced upregulation 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 AT1 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 activateG q/G 11 and hence stimulate PKC-dependent phosphorylation of the AT1 receptor.