Rap1b is required for normal platelet function and hemostasis in mice. J Clin Invest 2005 Mar;115(3):680-7
Date
02/08/2005Pubmed ID
15696195Pubmed Central ID
PMC546455DOI
10.1172/JCI22973Scopus ID
2-s2.0-14644400415 (requires institutional sign-in at Scopus site) 268 CitationsAbstract
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.
Author List
Chrzanowska-Wodnicka M, Smyth SS, Schoenwaelder SM, Fischer TH, White GC 2ndAuthors
Magdalena Chrzanowska PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinGilbert C. White MD Professor in the Medicine department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood Platelets
Bone Marrow Transplantation
Carotid Arteries
Collagen
Cyclic AMP
Embryo, Mammalian
Fibrinogen
Hemostasis
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Platelet Aggregation
Purinergic Antagonists
Regional Blood Flow
rap GTP-Binding Proteins
