title: Rap1b is required for normal platelet function and hemostasis in mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Chrzanowska-Wodnicka
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Fischer
authors.forename: Gilbert C
authors.initials: GC
authors.lastname: White
mesh_terms: 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*
chemical_list: D058914:Purinergic Antagonists; D005340:Fibrinogen; D003094:Collagen; D000242:Cyclic AMP; C492136:Rap1b protein, mouse; D020668:rap GTP-Binding Proteins