The Role of Rac1 in Glycoprotein Ib-IX-Mediated Signal Transduction and Integrin Activation
journal contributionposted on 2013-12-03, 00:00 authored by M. Keegan Delaney, Junling Liu, Yi Zheng, Michael C. Berndt, Xiaoping Du
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 (SFK), phosphoinositide 3-kinase (PI3K), and Akt, leading to activation of integrin α(IIb)β(3) 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 A(2) 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 SFK inhibitor-treated platelets but was unaffected by the PI3K inhibitor LY294002, 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. CONCLUSIONS: A Lyn-Vav-Rac1-PI3K-Akt pathway mediates von Willebrand factor-induced activation of integrin α(IIb)β(3) to promote GPIb-IX-dependent platelet activation.
This work is supported, in part, by National Heart, Lung, and Blood Institute/National Institutes of Health grants HL062350, HL068819, and HL080264 (to X.D.). M.K.D. is a recipient of the American Heart Association Midwest Affiliate Predoctoral Fellowship Award No. 11PRE7590050.
Publisher StatementThe original version is available through American Heart Association at DOI: 10.1161/ATVBAHA.112.254920. The final publication is available at http://atvb.ahajournals.org/
PublisherAmerican Heart Association