Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 115, Issue 3, Pages 680-687Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200522973
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Funding
- NHLBI NIH HHS [P01 HL045100, HL-45100] Funding Source: Medline
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Rap 1b, 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 (alpha(IIb)beta(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 alpha(IIb)beta(3) in response to stimulation with agonists and signaling downstream from the integrin C(alpha(IIb)beta(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.
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