Some key targets of activated Cdc42 are members of the WASp protein family. Human patients deficient in WASp suffer from Wiskott-Aldrich Syndrome, a severe form of immunodeficiency in which immune system cells have abnormal actin-based motility and platelets do not form normally. Although WASp itself is expressed only in blood cells and immune system cells, other more ubiquitous versions enable activated Cdc42 to enhance actin polymerization in many cell types. WASp proteins can exist in an inactive folded conformation and an activated open conformation. Association with Cdc42-GTP stabilizes the open form of WASp, enabling it to bind to the Arp 2/3 complex and strongly enhance its actin-nucleating activity (see Figure 16–16). In this way, activation of Cdc42 increases actin nucleation.
Rac-GTP also activates WASp family members. Additionally, it activates the cross-linking activity of the gel-forming protein filamin and inhibits the contractile activity of the motor protein myosin II. It thereby stabilizes lamellipodia and inhibits the formation of contractile stress fibers (Figure 16–85A).
Rho-GTP has a very different set of targets. Instead of activating the Arp 2/3 complex to build actin networks, Rho-GTP turns on formin proteins to construct parallel actin bundles. At the same time, Rho-GTP activates a protein kinase that indirectly inhibits the activity of cofilin, leading to actin filament stabilization. The same protein kinase inhibits a phosphatase acting on myosin light chains (see Figure 16–39). The consequent increase in the net amount of myosin light chain phosphorylation increases the amount of contractile myosin motor protein activity in the cell, enhancing the formation of tension-dependent structures such as stress fibers (Figure 16–85B).
In some cell types, Rac-GTP activates Rho, usually at a rate that is slow compared to Rac’s activation of the Arp 2/3 complex. This enables cells to use the Rac pathway to build a new actin structure while subsequently activating the Rho pathway to generate a contractility that builds up tension in this structure. This occurs, for example, during the formation and maturation of cell–cell contacts.
Figure 16–84 The dramatic effects of Cdc42, Rac, and Rho on actin organization in fibroblasts. In each case, the actin filaments have been labeled with fluorescent phalloidin. (A) Serum-starved fibroblasts have actin filaments primarily in the cortex, and relatively few stress fibers. (B) Microinjection of a constitutively activated form of Cdc42 causes the protrusion of many long filopodia at the cell periphery. (C) Microinjection of a constitutively activated form of Rac, a closely related monomeric GTPase, causes the formation of an enormous lamellipodium that extends from the  entire circumference of the cell.
(D) Microinjection of a constitutively activated form of Rho causes the rapid assembly of many prominent stress fibers. (From A. Hall, Science 279:509–514, 1998. With permission from AAAS.)
As we will explore in more detail below, the communication between the Rac and Rho pathways also facilitates maintenance of the large-scale differences between the cell front and the cell rear during migration.
Extracellular Signals Can Activate the Three Rho Protein Family Members