RAP GTPases and platelet integrin signaling

Platelets are highly specialized cells that continuously patrol the vasculature to ensure its integrity (hemostasis). At sites of vascular injury, they are able to respond to trace amounts of agonists and to rapidly transition from an anti-adhesive/patrolling to an adhesive state (integrin inside-out activation) required for hemostatic plug formation. Pathological conditions that disturb the balance in the underlying signaling processes can lead to unwanted platelet activation (thrombosis) or to an increased bleeding risk. The small GTPases of the RAP subfamily, highly expressed in platelets, are critical regulators of cell adhesion, cytoskeleton remodeling, and MAP kinase signaling. Studies by our group and others demonstrate that RAP GTPases, in particular RAP1A and RAP1B, are the key molecular switches that turn on platelet activation/adhesiveness at sites of injury. In this review, we will summarize major findings on the role of RAP GTPases in platelet biology with a focus on the signaling pathways leading to the conversion of integrins to a high-affinity state.