| First Author | Tsai HJ | Year | 2014 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 34 |
| Issue | 11 | Pages | 2404-12 |
| PubMed ID | 25212232 | Mgi Jnum | J:230476 |
| Mgi Id | MGI:5760122 | Doi | 10.1161/ATVBAHA.114.302602 |
| Citation | Tsai HJ, et al. (2014) Disabled-2 is required for efficient hemostasis and platelet activation by thrombin in mice. Arterioscler Thromb Vasc Biol 34(11):2404-12 |
| abstractText | OBJECTIVE: The essential role of platelet activation in hemostasis and thrombotic diseases focuses attention on unveiling the underlying intracellular signals of platelet activation. Disabled-2 (Dab2) has been implicated in platelet aggregation and in the control of clotting responses. However, there is not yet any in vivo study to provide direct evidence for the role of Dab2 in hemostasis and platelet activation. APPROACH AND RESULTS: Megakaryocyte lineage-restricted Dab2 knockout (Dab2(-/-)) mice were generated to delineate in vivo functions of Dab2 in platelets. Dab2(-/-) mice appeared normal in size with prolonged bleeding time and impaired thrombus formation. Although normal in platelet production and granule biogenesis, Dab2(-/-) platelets elicited a selective defect in platelet aggregation and spreading on fibrinogen in response to low concentrations of thrombin, but not other soluble agonists. Investigation of the role of Dab2 in thrombin signaling revealed that Dab2 has no effect on the expression of thrombin receptors and the outside-in signaling. Dab2(-/-) platelets stimulated by low concentrations of thrombin were normal in Galphaq-mediated calcium mobilization and protein kinase C activation, but were defective in Galpha(1)(2)/(1)(3)-mediated RhoA-ROCKII activation. The attenuated Galpha(1)(2)/(1)(3) signaling led to impaired ADP release, Akt-mammalian target of rapamycin and integrin alphaIIbbeta3 activation, fibrinogen binding, and clot retraction. The defective responses of Dab2(-/-) platelets to low concentrations of thrombin stimulation may contribute to the impaired hemostasis and thrombosis of Dab2(-/-) mice. CONCLUSIONS: This study sheds new insight in platelet biology and represents the first report demonstrating that Dab2 is a key regulator of hemostasis and thrombosis by functional interplay with Galpha(1)(2)/(1)(3)-mediated thrombin signaling. |
