Rap1b is required for normal platelet function and hemostasis in mice
Magdalena Chrzanowska-Wodnicka, … , Thomas H. Fischer, Gilbert C. White II
Magdalena Chrzanowska-Wodnicka, … , Thomas H. Fischer, Gilbert C. White II
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):680-687. https://doi.org/10.1172/JCI22973.
View: Text | PDF | Corrigendum
Article Hematology

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 αIIbβ3, 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 αIIbβ3 in response to stimulation with agonists and signaling downstream from the integrin αIIbβ3. 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

Magdalena Chrzanowska-Wodnicka, Susan S. Smyth, Simone M. Schoenwaelder, Thomas H. Fischer, Gilbert C. White II

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Prolonged tail bleeding time in Rap1b-null mice and in Rap1b-null bone m...
Prolonged tail bleeding time in Rap1b-null mice and in Rap1b-null bone marrow chimeras. Plotted are data from normal mice and bone marrow recipients with normal platelet counts in which the appropriate phenotype of the platelets was confirmed by Western blotting analysis. For each data set, the box shows the 25th to 75th percentile range and median, which in the KO group overlaps with the 75th percentile. Whiskers extend to the 5th and 95th percentiles and mean and SEM are plotted to the right of the box. WT/WT, chimeric normal mice transplanted with normal bone marrow; KO/WT, chimeric normal mice transplanted with Rap1b-null bone marrow.