Platelet Rho GTPase regulation in physiology and disease

Rho GTPases are master orchestrators of cytoskeletal dynamics and serve critical roles in platelet physiology to promote hemostasis or pathology in thrombotic, inflammatory and other disease states. Over the past 25 years, specific platelet cell biological outputs have been linked to the activities of Rho GTPases, including RhoA, Rac1, Cdc42, and RhoG in shape change and secretion as well as cytoskeletal assembly events underlying platelet aggregation and thrombus stability. Rho GTPases have also more recently been noted to serve more specialized roles in platelet function and to cooperate with one another in mediating essential platelet responses. The evolving molecular mechanisms regulating platelet Rho GTPase functions are increasingly complex, involving an interdependent array of signal transduction molecules, including several protein kinases as well as numerous Rho GEFs, GAPs, and GDI proteins such as LARG, ARHGEF6 (Cool-2, α-Pix), ARHGEF10, GIT1, ARHGAP17 (Nadrin, Rich1), OPHN1, and Ly-GDI. In this review, we provide an update of recent work and developing hypotheses further establishing more specialized as well as cooperative roles for Rho GTPases in platelet physiology and emerging regulatory and downstream effector mechanisms whereby Rho GTPases participate in platelet activation programs in physiology and an expanding set of platelet-associated disease states.