title: The role of Rac1 in glycoprotein Ib-IX-mediated signal transduction and integrin activation.
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 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.
  
  
  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.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, 835 South Wolcott Ave, Chicago, IL 60612, USA.
authors.forename: M Keegan
authors.initials: MK
authors.lastname: Delaney
authors.forename: Junling
authors.initials: J
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Michael C
authors.initials: MC
authors.lastname: Berndt
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Du
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013928:Thromboxane A2 / Q000378:metabolism; D013997:Time Factors; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009479:Neuropeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D051567:Proto-Oncogene Proteins c-vav; C484602:Rac1 protein, mouse; D014841:von Willebrand Factor; D013928:Thromboxane A2; D058539:Phosphatidylinositol 3-Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein