Binding of Endothelin-1 (ET-1) to its heterotrimeric G protein-coupled receptors stimulates various signaling cascades involving the activation of phospholipase C-beta, phospholipase D, protein kinase C (PKC), tyrosine kinases, Ca2+/calmodulin-dependent kinase (CaMKs), and Ras, a small molecular weight G-protein, but, the role of Rho GTPase remains unclear. In this project, we examined whether RhoA contributes to the ET-1-induced signaling cascade to c-fos SRE activation in Rat-2 fibroblast cells. Our results demonstrate that Rho activation is critical for the signal transduction of ET-1 to c-fos SRE.