Ras and Rho Teamwork Favors Cell Transformation

Abstract

The Rho family of small gunaosine triphosphate (GTP)-binding proteins, including Rho, Rac, and Cdc42, regulates actin cytoskeleton dynamics. These proteins are also required for oncogenic Ras to transform cells. However, transformed Swiss 3T3 cells usually lack the actin stress fibers that result from Rho activation, leaving open the question of Rho activity in transformation. Sahai et al. report that there is indeed an increase in Rho-GTP in these fibroblasts when they are transformed with oncogenic Ras. However, this increase is not the direct consequence of Ras-regulated signaling pathways, but rather results indirectly by a selection process that establishes the transformed phenotype. Elevated Map kinase activity that results from oncogenic Ras has been known to increase expression of a cell-cycle inhibitor called p21/Waf. The authors now show that Rho-GTP decreases p21/Waf expression to levels that permit cell growth. The selection of highly proliferative cells transformed by Ras results in accumulation of cells with increased Rho activity. Rho-GTP is apparently also uncoupled from affecting the actin cytoskeleton because of a decrease in access to its downstream effectors ROCK and Rho kinase. This decrease in effector targets results from sustained Map kinase activity in transformed cells. Hence, there is reciprocal cross-talk between the Ras and Rho signaling pathways in transformation. The authors note that selective pressures that determine the activity of Rho family proteins in transformed cells will likely vary depending on the cell type.E. Sahai, M.F. Olson, C.J. Marshall, Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. EMBO J. 20, 755-766 (2001). [Abstract] [Full Text]