Insulin-like growth factor-1 regulates platelet activation through PI3-Kalpha isoform.
Platelets release insulin-like growth factor-1 (IGF-1) from alpha 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(z) 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 (PI3-K) inhibitor wortmannin, suggesting a critical regulation by PI3-K. Moreover, the potentiating effect of IGF-1 was abolished by the presence of PI3-K p110alpha inhibitor PIK-75. Stimulation of platelets with IGF-1 resulted in phosphorylation of Akt, a downstream effector of PI3-K, which was completely inhibited by wortmannin. IGF-1-induced Akt phosphorylation was abolished by PIK-75 suggesting the contribution of PI3-K p110alpha 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 PI3-K p110alpha.
Kim
Soochong
S
Department of Physiology and Pharmacology and the Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Garcia
Analia
A
Jackson
Shaun P
SP
Kunapuli
Satya P
SP
D002478:Cells, Cultured; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015539:Platelet Activation; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction