A Rho GTPase switch can be regulated by three classes of regulators: GEFs, GAPs, and GDIs. In the canonical model of the Rho GTPase cycle (Figure 1A, left), GEFs promote GDP/GTP exchange, thereby activating Rho GTPases. In contrast, GAPs promote GTP hydrolysis, thereby inactivating Rho GTPases. GDIs sequester GDP-bound GTPases from GEFs and keep them inactive; however, GDIs can also sequester GTP-bound GTPases from GAPs and keep them active. In this model, the Rho GTPase cycle functions as a simple ON/OFF switch and Rho activation is transiently elevated upon stimulation (Figure 1A, right).
Figure 1  Representation of the models of Rho GTPase cycle regulation (left) and simulations of their Rho activation dynamics (right). The activation levels of GTPases were defined as the concentration of the GTP-Rho/Effector complex. A) The canonical model of the Rho GTPase cycle in which GDIs inhibit the activities of GEFs and GAPs by sequestering GTPase. B) The GDI-integrated model of the Rho GTPase cycle in which GDIs inhibit the activities of GEFs and GAPs not only by sequestering GTPase but also by interacting with GEFs and GAPs. C) GDI/GEF interaction was removed from the GDI-integrated model. D) GDI/GAP interaction was removed from the GDI-integrated model. All parameters and reactions in the models are shown in Additional file 1: Tables S1 and S2. Reaction numbers (re#) correspond to the reaction numbers in Additional file 1: Table S2.