[HTML][HTML] Rap1b is required for normal platelet function and hemostasis in mice

M Chrzanowska-Wodnicka, SS Smyth… - The Journal of …, 2005 - Am Soc Clin Investig
The Journal of clinical investigation, 2005Am Soc Clin Investig
Rap1b, an abundant small GTPase in platelets, becomes rapidly activated upon stimulation
with agonists. Though it has been implicated to act downstream from G protein–coupled
receptors (GPCRs) and upstream of integrin α IIb β 3, the precise role of Rap1b in platelet
function has been elusive. Here we report the generation of a murine rap1b knockout and
show that Rap1b deficiency results in a bleeding defect due to defective platelet function.
Aggregation of Rap1b-null platelets is reduced in response to stimulation with both GPCR …
Rap1b, an abundant small GTPase in platelets, becomes rapidly activated upon stimulation with agonists. Though it has been implicated to act downstream from G protein–coupled receptors (GPCRs) and upstream of integrin α IIb β 3, the precise role of Rap1b in platelet function has been elusive. Here we report the generation of a murine rap1b knockout and show that Rap1b deficiency results in a bleeding defect due to defective platelet function. Aggregation of Rap1b-null platelets is reduced in response to stimulation with both GPCR-linked and GPCR-independent agonists. Underlying the defective Rap1b-null platelet function is decreased activation of integrin α IIb β 3 in response to stimulation with agonists and signaling downstream from the integrin α IIb β 3. In vivo, Rap1b-null mice are protected from arterial thrombosis. These data provide genetic evidence that Rap1b is involved in a common pathway of integrin activation, is required for normal hemostasis in vivo, and may be a clinically relevant antithrombotic therapy target.
The Journal of Clinical Investigation