Uncovering Bistability in the Rac1/RhoA Signaling Network Through Integrating Computational Modeling and...

The members of the Rho family of small guanosine triphosphatases (GTPases), Rac1 and RhoA, play critical roles in the regulation of cell migration, actin dynamics, and cytoskeletal system. It has been long known that a mutual inhibition relationship exists between Rac1 and RhoA, and the Rac1/RhoA circuitry has been theoretically predicted to be capable of displaying bistability, a phenomenon whereby a system could settle in either one of the two stable steady states. However, it was only until recently that bistable behavior was demonstrated experimentally both at the biochemical and cellular phenotypic levels, through an integrative approach combining computational modeling and wet-lab experimentation. Here, we describe how such systems biology approaches could be employed to uncover bistability and its hallmark features, using the Rac1/RhoA network as an illustrative example. This may provide guidance for future work aimed at identifying bistable behaviors in other cellular processes.