Relative contribution of G-protein-coupled pathways to protease-activated receptor-mediated Akt phosphorylation in platelets.
Blood
; 107(3): 947-54, 2006 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-16223779
ABSTRACT
Protease-activated receptors (PARs) activate Gq and G(12/13) pathways, as well as Akt (protein kinase B [PKB/Akt]) in platelets. However, the relative contribution of different G-protein pathways to Akt phosphorylation has not been elucidated. We investigated the contribution of Gq and G(12/13) to Gi/Gz-mediated Akt phosphorylation downstream of PAR activation. Selective G(12/13) activation failed to cause Akt phosphorylation in human and Galpha q-deficient mouse platelets. However, supplementing Gi/Gz signaling to G(12/13) caused significant increase in Akt phosphorylation, confirming that G(12/13) potentiates Akt phosphorylation. Inhibition of PAR-mediated Akt phosphorylation in the presence of the Gq-selective inhibitor YM-254890 was restored to the normal extent achieved by PAR agonists if supplemented with Gi signaling, indicating that Gq does not have any direct effect on Akt phosphorylation. Selective G(12/13) activation resulted in Src kinase activation, and Akt phosphorylation induced by costimulation of G(12/13) and Gi/Gz was inhibited by a Src kinase inhibitor but not by a Rho kinase inhibitor. These data demonstrate that G(12/13), but not Gq, is essential for thrombin-induced Akt phosphorylation in platelets, whereas Gq indirectly contributes to Akt phosphorylation through Gi stimulation by secreted ADP. G(12/13) activation might mediate its potentiating effect through Src activation, and Src kinases play an important role in thrombin-mediated Akt phosphorylation.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Plaquetas
/
Transducción de Señal
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Subunidades alfa de la Proteína de Unión al GTP G12-G13
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Subunidades alfa de la Proteína de Unión al GTP Gq-G11
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Receptores Proteinasa-Activados
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Proteínas Proto-Oncogénicas c-akt
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Blood
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos