Rac1 and RhoA: Networks, loops and bistability

Abstract

Cell migration requires a precise temporal and spatial coordination of several processes which allow the cell to efficiently move. The extension and retraction of membrane protrusion, as well as adhesion are controlled by the Rho-family small GTPases. Two members of the family, Rac1 and RhoA, can show opposite behaviors and spatial localisations, with RhoA being active toward the rear of the cell and regulating its retraction during migration, whereas Rac1 is active toward the front of the cell. In addition to the spatial segregation, RhoA and Rac1 activity at the leading edge of the cells has an element of temporal segregation, with RhoA and Rac1 activities peaking at separate points during the migratory cycle of protrusion and retraction. Elements of this separation have been explained by the presence of 2 mutually inhibitory feedbacks, where Rac1 inhibits RhoA and RhoA in turn can inhibit Rac1. Recently, it was shown that Rac1 and RhoA activity and downstream signaling respond in a bistable manner to perturbations of this network.

Keywords: PAK inhibition; Rac1; RhoA; bistable switches; cell motility; mathematical modeling.

Figure 1.

Model simulations of network dynamics under different conditions. (A) Cell-specific abundances of key network components in different cell-types determined by Mass Spectrometry (analyzed from ref. 14). (B) Simulated responses to increasing Rac1 inhibitor (IPA-3), plotted for RhoA-GTP as an example, for different cell types. The inbox shows the response for the remaining cells which display non-sigmoidal behaviors. (C) Graphical illustration of targeted therapeutic strategy that utilises an irreversible switch. (D) Simulations showing the sensitivity of the bistable switch to the concentration of Rac1. All model simulations were performed using our model published in ref. . The concentration units for RhoA-GTP are in μM.

Figure 2.

Subcellular site-specific simulations of network behaviors. (A, B) Simulated responses to increasing PAK inhibitor (IPA-3) for active Rac1 and RhoA as the concentrations of Rac1, RhoA and Rac1s GAP are simultaneously altered. (C) Illustrative simulations of the network responses at specific subcellular sites characterized by different expression profiles of the network nodes. All model simulations were performed using our model published in ref. . The concentration units for RhoA-GTP are in μM.