The role of Rac1 in glycoprotein Ib-IX-mediated signal transduction and integrin activation

M. Keegan Delaney, Junling Liu, Yi Zheng, Michael C. Berndt, Xiaoping Du

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27 Citations (Scopus)

Abstract

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 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 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. Conclusion-A Lyn-Vav-Rac1-PI3K-Akt pathway mediates von Willebrand factor-induced activation of integrin αIIbβ 3 to promote GPIb-IX-dependent platelet activation.

Original languageEnglish
Pages (from-to)2761-2768
Number of pages8
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume32
Issue number11
DOIs
Publication statusPublished - Nov 2012
Externally publishedYes

Keywords

  • Glycoprotein Ib-IX
  • Platelet
  • Platelet adhesion
  • Rac1
  • Von Willebrand factor

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