Insulin-like growth factor-1 regulates platelet activation through PI3-Kα isoform

Platelets release insulin-like growth factor-1 (IGF-1) from a granules upon activation. We have investigated the regulation of IGF-1 in G(i)-dependent pathways leading to Akt activation and the role of IGF-1 in platelet activation. IGF-1 alone failed to induce platelet aggregation, but IGF-1 potentiated 2-MeSADP-induced platelet aggregation in a concentration-dependent manner. IGF-1 triggered platelet aggregation in combination with selective P2Y(1) receptor activation. IGF-1 also caused platelet aggregation without shape change when combined with selective G, stimulation by epinephrine, suggesting the role of IGF-1 in platelet aggregation by supplementing G(i) pathways. The potentiating effect of IGF-1 was not affected by intracellular calcium chelation. Importantly, IGF-1 was unable to potentiate platelet aggregation by the phosphatidylinositol 3-kinase (P13-K) inhibitor wortmannin, suggesting a critical regulation by P13-K. Moreover, the potentiating effect of IGF-1 was abolished by the presence of P13-K p110 alpha inhibitor PIK-75. Stimulation of platelets with IGF-1 resulted in phosphorylation of Akt, a down-stream effector of P13-K, which was completely inhibited by wortmannin. IGF-1-induced Akt phosphorylation was abolished by PIK-75 suggesting the contribution of P13-K P110 alpha for activation of Akt by IGF-1. These results demonstrate that IGF-1 plays a role in potentiating platelet aggregation by complementing G(i)- but not G(q)-signaling pathways via P13-K p110 alpha.