The role of Rac1 in glycoprotein Ib-IX-mediated signal transduction and integrin activation.
Arterioscler Thromb Vasc Biol
; 32(11): 2761-8, 2012 Nov.
Article
em En
| MEDLINE
| ID: mdl-22995516
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)ß(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 ANDRESULTS:
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)ß(3) to promote GPIb-IX-dependent platelet activation.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Plaquetas
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Neuropeptídeos
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Transdução de Sinais
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Adesividade Plaquetária
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Agregação Plaquetária
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Complexo Glicoproteico GPIIb-IIIa de Plaquetas
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Complexo Glicoproteico GPIb-IX de Plaquetas
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Proteínas rac de Ligação ao GTP
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article