Role of Rac1 in Glycoprotein Ib-IX Mediated Signal Transduction and Integrin Activation
Objective—The platelet receptor for von Willebrand factor, the glycoprotein Ib-IX (GPIb-IX) complex, mediates platelet adhesion at sites of vascular injury and transmits signals leading to platelet activation. von Willebrand factor/GPIb-IX interaction sequentially activates the Src family kinase Lyn, phosphoinositide 3-kinase (PI3K), and Akt, leading to activation of integrin αIIbβ3 and integrin-dependent stable platelet adhesion and aggregation. It remains unclear how Lyn activates the PI3K/Akt pathway after ligand binding to GPIb-IX.
Methods and Results—Using platelet-specific Rac1−/− mice and the Rac1 inhibitor NSC23766, we examined the role of Rac1 in GPIb-IX–dependent platelet activation. Rac1−/− mouse platelets and NSC23766-treated human platelets were defective in GPIb-dependent stable adhesion to von Willebrand factor under shear stress, integrin activation, thromboxane A2 synthesis, and platelet aggregation. Interestingly, GPIb-induced activation of Rac1 and the guanine nucleotide exchange factor for Rac1, Vav, was abolished in both Lyn−/− and PP2 treated platelets but was unaffected by the PI3K inhibitor LY-294002, indicating that Lyn mediates activation of Vav and Rac1 independently of PI3K. Furthermore, GPIb-induced activation of Akt was abolished in Rac1-deficient platelets, suggesting that Rac1 is upstream of the PI3K/Akt pathway.
Conclusion—A Lyn/Vav/Rac1/PI3K/Akt pathway mediates von Willebrand factor induced activation of integrin αIIbβ3 to promote GPIb-IX dependent platelet activation.
- Received June 8, 2012.
- Accepted September 5, 2012.
- © 2012 American Heart Association, Inc.