Regulatory models of RhoA suppression by dematin, a cytoskeletal adaptor protein

Abstract

Cell motility, adhesion and actin cytoskeletal rearrangements occur upon integrin-engagement to the extracellular matrix and activation of the small family of Rho GTPases, RhoA, Rac1 and Cdc42. The activity of the GTPases is regulated through associations with guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and guanine dissociation inhibitors (GDIs). Recent studies have demonstrated a critical role for actin-binding proteins, such as ezrin, radixin and moesin (ERM), in modulating the activity of small GTPases through their direct associations with GEFs, GAPs and GDI's. Dematin, an actin binding and bundling phospho-protein was first identified and characterized from the erythrocyte membrane, and has recently been implicated in regulating cell motility, adhesion and morphology by suppressing RhoA activation in mouse embryonic fibroblasts. Although the precise mechanism of RhoA suppression by dematin is unclear, several plausible and hypothetical models can be invoked. Dematin may bind and inhibit GEF activity, form an inactive complex with GDI-RhoA-GDP, or enhance GAP function. Dematin is the first actin-binding protein identified from the erythrocyte membrane that participates in GTPase signaling, and its broad expression suggests a conserved function in multiple tissues.

Figure 1

Hypothetical models of dematin mediated regulation of RhoA signaling. (A) Dematin has been shown to bind the DH domain of RasGRF2, but does not modulate Rac1 or Ras activation through RasGRF2. In several yeast-2-hybrid RasGRF2 clones, an insert from the GEFD2 domain of the RhoA GEF, Trio, was identified. It is possible that dematin may bind to and inhibits the RhoA GEF activity on Trio. (B) Dematin may complex with GDI and inactive RhoA-GDP, by tethering GDI to the actin cytoskeleton. The release of dematin from the cytoskeleton results in RhoA-GDP release and activation. (C) Dematin may also act to spatially localize RhoGAP to enhance the activity on RhoA-GTP, which in turn results in RhoA suppression.