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J. Biol. Chem., Vol. 279, Issue 6, 4186-4195, February 6, 2004

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Akt Activation in Platelets Depends on G_i Signaling Pathways^*

Soochong Kim, Jianguo Jin, and Satya P. Kunapuli¶||

From the Department of Physiology, the Department of Pharmacology, and the ^¶Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

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 Thr³⁰⁸ and Ser⁴⁷³ phosphorylation of Akt, which results in its activation. This phosphorylation and activation of Akt were dramatically inhibited in the presence of AR-C69931MX, a P2Y₁₂ 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 G_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 P2Y₁ receptor. However, ADP caused Akt phosphorylation in G_q- and P2Y₁-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.

Received for publication, June 11, 2003 , and in revised form, November 17, 2003.

^* This work was supported by Research Grants HL60683 and HL64943 from the National Institutes of Health (to S. P. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Physiology, Temple University School of Medicine, 3420 N. Broad St., Philadelphia, PA 19140. Tel.: 215-707-4615; Fax: 215-707-4003; E-mail: spk{at}temple.edu.

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