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

Abstract

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 (Ras^V12) in Rat1 fibroblasts. The cells expressing Ras^V12 showed the severe disruption of actin stress fibers and cell adhesions. The coexpression of dominant active form of Rho (Rho^V14) 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 Rat1 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 Ras^V12. These results suggest that the Rho-Rho-kinase pathway may be inactivated in the cells expressing Ras^V12, and this may contribute to oncogenic Ras-induced transformation.