Mas oncogene signaling and transformation require the small GTP-binding protein Rac.
The Mas oncogene encodes a novel G-protein-coupled receptor that was identified originally as a transforming protein when overexpressed in NIH 3T3 cells. The mechanism and signaling pathways that mediate Mas transformation have not been determined. We observed that the foci of transformed NIH 3T3 cells caused by Mas were similar to those caused by activated Rho and Rac proteins. Therefore, we determined if Mas signaling and transformation are mediated through activation of a specific Rho family protein. First, we observed that, like activated Rac1, Mas cooperated with activated Raf and caused synergistic transformation of NIH 3T3 cells. Second, both Mas- and Rac1-transformed NIH 3T3 cells retained actin stress fibers and showed enhanced membrane ruffling. Third, like Rac, Mas induced lamellipodium formation in porcine aortic endothelial cells. Fourth, Mas and Rac1 strongly activated the JNK and p38, but not ERK, mitogen-activated protein kinases. Fifth, Mas and Rac1 stimulated transcription from common DNA promoter elements: NF-kappaB, serum response factor (SRF), Jun/ATF-2, and the cyclin D1 promoter. Finally, Mas transformation and some of Mas signaling (SRF and cyclin D1 but not NF-kappaB activation) were blocked by dominant negative Rac1. Taken together, these observations suggest that Mas transformation is 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.
Zohn
I E
IE
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill 27599-7038, USA.
Symons
M
M
Chrzanowska-Wodnicka
M
M
Westwick
J K
JK
Der
C J
CJ
D016475:3T3 Cells; D000199:Actins / Q000502:physiology; D000818:Animals; D002471:Cell Transformation, Neoplastic; D003599:Cytoskeleton / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf; D043562:Receptors, G-Protein-Coupled; D015682:Retroviridae Proteins, Oncogenic / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D000199:Actins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D015682:Retroviridae Proteins, Oncogenic; D019908:Proto-Oncogene Proteins c-raf; C107753:proto-oncogene protein v-RAF1, pig; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein