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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.
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Article Hematology

Rap1b is required for normal platelet function and hemostasis in mice

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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

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Figure 1

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Targeted inactivation of the rap1b gene. (A) The murine rap1b gene consi...
Targeted inactivation of the rap1b gene. (A) The murine rap1b gene consists of 6 coding (bands) and 1 untranslated exon (3′ UTR, open box). (B) The targeting vector contains 7.8 kb of genomic DNA flanking the neomycin-resistance cassette (neo). TK, thymidine kinase. (C) After homologous recombination, the neo cassette replaces the complete coding sequence of the rap1b gene. (D) Southern blot analysis of mouse tail DNA from heterozygous intercrosses digested with SspI and KpnI using a probe (P) that detects 5.5-kb and 9-kb fragments in the wild-type and knockout allele, respectively. (E) Western blot analysis of protein expression in platelets of indicated genotype. (F) Morphology of E15.5 wild-type (+/+) and Rap1b-null (–/–) embryos. Scale bar: 1 mm. E, EcoRI; H, HinDIII; K, KpnI; S, SspI.
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