Outside-in signaling to the actomyosin cytoskeleton via Rho-family small GTPases. The Rho GTPases are particularly important for platelet spreading and retraction. (A) The activation status of the 3 Rho-family small GTPases, Rac, Cdc42, and RhoA is regulated by GAPs and GEFs downstream of activated integrins. When GTP-bound and active, these small GTPases signal to the actomyosin cytoskeleton via multiple effector proteins. Cdc42 and Rac can promote Arp2/3-mediated actin polymerization via WASP and WAVE proteins, respectively, whereas RhoA promotes MLC phosphorylation via ROCK-mediated inhibition of MLC phosphatase (MLCP). These small GTPases may also regulate actin dynamics via proteins such as cofilin, and via formins. (B) In platelets, regulation of RhoA activity coordinates platelet spreading and subsequent clot retraction, as discussed in panels i and ii. Hashed lines represent phosphorylation events; yellow circles represent activating phosphorylation; orange circles represent inhibitory phosphorylation.