Possible involvement of the inactivation of the Rho-Rho-kinase pathway in oncogenic Ras-induced transformation.

Recent evidence has strongly suggested the involvement of Rho family small guanosine triphosphatases (GTPases) in Ras-induced transformation. To further clarify the role of Rho family GTPases in Ras-induced transformation, we examined the effects of dominant active or dominant negative forms of Rho family GTPases on the morphological changes induced by oncogenic Ras (RasV12) in Rat1 fibroblasts. The cells expressing RasV12 showed the severe disruption of actin stress fibers and cell adhesions. The coexpression of dominant active form of Rho (RhoV14) reverted not only the formation of stress fibers and focal adhesions but also cell-cell adhesions in Ras-transformed Rat1 cells. In addition, the coexpression of constitutively activated Rho-kinase, a downstream effector of Rho, restored the assembly of stress fibers and focal adhesions. Treatment of Ratl cells with lysophosphatidic acid, which is known to activate the Rho-Rho-kinase pathway, enhanced the stress fiber formation, whereas it failed to induce the stress fiber formation in the cells expressing RasV12. These results suggest that the Rho-Rho-kinase pathway may be inactivated in the cells expressing RasV12, and this may contribute to oncogenic Ras-induced transformation.