Akt activation in platelets depends on Gi signaling pathways

被引:152
作者
Kim, S
Jin, JG
Kunapuli, SP
机构
[1] Temple Univ, Sch Med, Dept Physiol, Philadelphia, PA 19140 USA
[2] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA
[3] Temple Univ, Sch Med, Sol Sherry Thrombosis Res Ctr, Philadelphia, PA 19140 USA
关键词
D O I
10.1074/jbc.M306162200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The serine-threonine kinase Akt has been established as an important signaling intermediate in regulating cell survival, cell cycle progression, as well as agonist-induced platelet activation. Stimulation of platelets with various agonists including thrombin results in Akt activation. As thrombin can stimulate multiple G protein signaling pathways, we investigated the mechanism of thrombin-induced activation of Akt. Stimulation of platelets with a PAR1-activating peptide (SFLLRN), PAR4-activating peptide (AYPGKF), and thrombin resulted in Thr(308) and Ser(473) phosphorylation of Akt, which results in its activation. This phosphorylation and activation of Akt were dramatically inhibited in the presence of AR-C69931MX, a P2Y(12) receptor-selective antagonist, or GF 109203X, a protein kinase C inhibitor, but Akt phosphorylation was restored by supplemental G(i) or G(z) signaling. Unlike wild-type mouse platelets, platelets from Galpha(q)-deficient mice failed to trigger Akt phosphorylation by thrombin and AYPGKF, whereas Akt phosphorylation was not affected by these agonists in platelets from mice that lack P2Y(1) receptor. However, ADP caused Akt phosphorylation in Galpha(q) and P2Y(1)-deficient platelets, which was completely blocked by AR-C69931MX. In contrast, ADP failed to cause Akt phosphorylation in platelets from mice treated with clopidogrel, and thrombin and AYPGKF induced minimal phosphorylation of Akt, which was not affected by AR-C69931MX in these platelets. These data demonstrate that G(i), but not G(q) or G(12/13), signaling pathways are required for activation of Akt in platelets, and G(i) signaling pathways, stimulated by secreted ADP, play an essential role in the activation of Akt in platelets.
引用
收藏
页码:4186 / 4195
页数:10
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