MAS ONCOGENE SIGNALING AND TRANSFORMATION REQUIRE THE SMALL GTP-BINDING PROTEIN RAC

The Mas oncogene encodes a novel G protein-coupled receptor that was i dentified originally as a transforming protein when overexpressed in N IH 3T3 cells. The mechanism and signaling pathways that mediate Mas tr ansformation have not been determined. We observed that the foci of tr ansformed NIH 3T3 cells caused by Mas were similar to those caused by activated Rho and Rac proteins. Therefore, we determined if Mas signal ing and transformation are mediated through activation of a specific R ho family protein. First, we observed that, like activated Rad, Mas co operated with activated Raf and caused synergistic transformation of N IH 3T3 cells. Second, both Mas-and Rad-transformed NIH 3T3 cells retai ned actin stress fibers and showed enhanced membrane ruffling. Third, like Rac, Mas induced lamellipodium formation in porcine aortic endoth elial cells. Fourth, Mas and Rac1 strongly activated the JNK and p38, but not ERK, mitogen-activated protein kinases. Fifth, Mas and Rac1 st imulated transcription from common DNA promoter elements: NF-kappa B, serum response factor (SRF), Jun/ATF-2, and the cyclin D1 promoter. Fi nally, Mas transformation and some of Mas signaling (SRF and cyclin D1 but not NF-kappa B activation) were blocked by dominant negative Rac1 . Taken together, these observations suggest that Mas transformation i s mediated in part by activation of Rac-dependent signaling pathways. Thus, Rho family proteins are common mediators of transformation by a diverse variety of oncogene proteins that include Ras, Dbl family, and G-protein-coupled oncogene proteins.