Rac1 activation comes full circle.

The Rac1 small GTPase is responsive to a large array of extracellular signals and in turn controls a wide variety of cellular functions—including actin dynamics. New findings add an additional layer of intricacy to the already complex process of regulating Rac1 activity, via a positive feedback loop involving the actin-binding protein coronin 1A, the Rac1 exchange factor ArhGEF7, the Rac1 effector Pak1 and the Rac1 inhibitor RhoGDIa. This complex shows remarkable versatility, integrating Rac1 translocation, release from RhoGDI and, possibly, nucleotide exchange. Rac1 orchestrates the assembly of actin-based structures, including lamellipodia and invadopodia, which are involved in directional processes such as cell migration and invasion (Chuang et al, 2004). Precise spatiotemporal control of Rac1 activation is critically important for these events (Bustelo et al, 2007; Berzat and Hall, 2010). Accordingly, localized Rac1 activity is subject to complex control mechanisms that involves tight regulation of GDP dissociation inhibitors (RhoGDIs) and guanine nucleotide exchange factors (Rho GEFs) (Rossman et al, 2005; Garcia-Mata et al, 2011). Binding of Rac1 to RhoGDIs blocks its interaction with GEFs, downstream effectors and GTPase activating proteins, which stimulate intrinsic GTP hydrolysis. In addition, RhoGDIs, by shielding the GTPase prenyl group that serves as a lipid anchor to phospholipid bilayers, prevents access of Rac1 to membrane binding sites. The interaction between Rac1 and RhoGDI is regulated by protein kinases and phospholipids. For example, phosphorylation of RhoGDI by the Rac1 effector Pak1 weakens its interaction with Rac1 (Garcia-Mata et al, 2011), raising the possibility of a positive feedback loop that enhances Rac1 activation. GEFs are also regulated by multiple mechanisms, including phosphorylation and interaction with phosphatidylinositol lipids and an array of protein binding partners (Rossman et al, 2005). Another mode of regulating localized Rac1 activation involves a number of docking proteins, that include ArhGEF7 (also known as Cool1 or bPIX) (ten Klooster et al, 2006). Binding of Rac1 to ArhGEF7 directs Rac1 to the plasma membrane and focal adhesions in the leading edge of migrat-