Abstract
Rho-associated coiled-coil containing protein kinase 1 (ROCK1) is a key downstream effector of the small GTPase RhoA. Targeting ROCK1 has shown promising clinical potential in cancer, cardioprotection, hypertension, diabetes, neuronal regeneration, and stem cell biology. General working hypothesis in previous studies has centered on the function of ROCK1 as a downstream sequence in the RhoA signaling pathway. In this study, the effects of the direct inhibition of ROCK1 on the activity of upstream RhoA and Rac1 were examined using a combined pharmacological and genetic approach. We report an intriguing mechanism by which the inhibition of ROCK1 indirectly diminishes the activity of upstream RhoA through the stimulation of Tiam1-induced Rac1 activity. This novel feedback mechanism, in which ROCK1 mediates upstream Rac1 and RhoA activity, offers considerable insight into the diverse effects of ROCK1 on the functional balance of the Rho family of small GTPases, which regulates actin cytoskeleton reorganization processes and the resulting overall behavior of cells.