Multistability in GTPase-Based Decision Circuits

Abstract

Cell fate decisions during embryonic development and tumorigenesis pose a major research challenge in modern developmental and cancer biology. Cell fate decisions between different phenotypes are regulated by multistable gene circuits that give rise to the coexistence of several stable states (phenotypes). GTPases are molecular switches, which toggle between GTP-bound active state and GDP-bound inactive state. GTPase-based gene regulatory circuits play a crucial role during embryonic development and tumorigenesis. An archetypal example is the RhoA-Rac1 circuit that regulates cell fate determination between amoeboid and mesenchymal phenotype. Here, we introduced a biologically consistent, yet tractable, theoretical framework to model and investigate GTPase-based gene regulatory circuits. We show that although the modeling approach incorporates the details of GTPase activation/inactivation dynamics (GTP loading and hydrolysis reactions), it yields relatively simple effective circuit models. The efficiency of this new approach is illustrated for the specific case of the Rac1-RhoA mutually inhibitory feedback loop. We found that this simple two components unit can yield, for realistic circuit parameters, elaborate multistability with the coexistence of diverse stable states. This can explain the experimentally observed plasticity of cell migration and the existence of diverse phenotypes including blebby amoeboid, pseudeopodia amoeboid, lobopodia, blebby lamellipodia, mesenchymal lamellipodia, mesenchymal filopodia.