Rho protein crosstalk: another social network?

Abstract

Many fundamental processes in cell biology are regulated by Rho GTPases, including cell adhesion, migration and differentiation. While regulating cellular functions, members of the Rho protein family cooperate or antagonize each other. The resulting molecular network exhibits many levels of interaction dynamically regulated in time and space. In the first part of this review we describe the main mechanisms of this crosstalk, which can occur at three different levels of the pathway: (i) through regulation of activity, (ii) through regulation of protein expression and stability, and (iii) through regulation of downstream signaling pathways. In the second part we illustrate the importance of Rho protein crosstalk with two examples: integrin-based adhesion and cell migration.

Figure 1. Modalities of regulation between two Rho proteins

Diagram showing how two Rho proteins (R1 and R2) can negatively (A) or positively (B) regulate one another. An example is indicated for each type of modality (via a GEF or a GAP, via GDI, via the regulation of the same downstream signaling pathway).

Figure 2. Crosstalk between RhoA and Rac1

Schematic diagram showing the crosstalk mechanisms between RhoA and Rac1.

Figure 3. Rho protein crosstalk during cell migration

A diagram of a migrating fibroblast is shown depicting zones of Rho protein activation and crosstalk. 1. Cdc42 controls formation of exploratory filopodia. 2. RhoA activity has been detected at the leading edge of lamellipodia where it may contribute to actin polymerization, directly via mDia or indirectly through mDia activating Rac1. 3. Behind the narrow zone of high RhoA activity, a wider zone of high Rac1 activity has been described. This may arise downstream from integrin engagement. Alternatively, Cdc42 and RhoG may contribute to Rac1 activation. This, in turn, inhibits RhoA and promotes nascent adhesion formation associated with actin-based protrusion. 4. RhoA generates ROCK-mediated contractility and inhibits Rac1, leading to adhesion maturation. 5. RhoA prevents inappropriate lateral protrusion by inhibiting Rac1 through ROCK2. 6. RhoA promotes cell body retraction through ROCK1-mediated myosin II stimulation. 7. Rac1 activation at the tail has been described but its function in this area is unknown.