Rap1b is required for normal platelet function and hemostasis in mice.
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 alpha IIbbeta3, 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 alphaIIbbeta3 in response to stimulation with agonists and signaling downstream from the integrin alpha IIbbeta3. 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.
Chrzanowska-Wodnicka
Magdalena
M
Department of Medicine and Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. Magdalena_Wodnicka@med.unc.edu.
Smyth
Susan S
SS
Schoenwaelder
Simone M
SM
Fischer
Thomas H
TH
White
Gilbert C
GC
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002339:Carotid Arteries / Q000473:pathology / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005340:Fibrinogen / Q000378:metabolism; D006487:Hemostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000502:physiology; D058914:Purinergic Antagonists; D012039:Regional Blood Flow; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D058914:Purinergic Antagonists; D005340:Fibrinogen; D003094:Collagen; D000242:Cyclic AMP; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins