Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kα pathway
Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3Kα pathway
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DOI：
10.1182/blood-2006-10-050633
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发表时间：
2007-12-15
期刊：
影响因子：
20.3
通讯作者：
Hers, Ingeborg
中科院分区：
文献类型：
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作者：
Hers, Ingeborg
由于胰岛素样生长因子-1（IGF-1）存在于血小板颗粒中，其受体在血小板表面表达，因此可能有助于血小板反应的放大和心血管疾病的发病机制。然而，参与IGF-1调节血小板功能的功能和信号通路目前尚不清楚。在这里，我报告说，IGF-1刺激血小板的结果在1至100 nM的范围内的IGF受体的剂量依赖性磷酸化。IGF受体的磷酸化是快速和持续的，在1分钟内达到最大磷酸化。此外，IGF-1刺激胰岛素受体底物-1（IRS-1）和IRS-2的酪氨酸磷酸化及其与磷酸肌醇-3激酶（PI 3 K）p85亚基的结合。IGF-1刺激IRS-1和IRS-2的酪氨酸磷酸化以及随后的p85结合是瞬时的，并且先于Ser 473上的蛋白激酶B（PK B）的磷酸化。PAR-1介导的血小板聚集被IGF-1增强，这种增强作用与PKB磷酸化一起被PI 3 K α抑制剂PI-103和PIK-75消除。重要的是，IGF受体抑制剂NVP-AEW 541和中和抗体α IR 3抑制SFLLRN刺激的聚集，暗示IGF-1参与血小板功能的自分泌调节。这些结果表明，IGF-1激活IGF受体/IRS/PI 3 K/PKB途径，并且PI 3 K α对于IGF-1对血小板应答的增强作用是必需的。
As insulin-like growth factor-1 (IGF-1) is present in the a granules of platelets and its receptor is expressed on the platelet surface, it may contribute to the amplification of platelet responses and pathogenesis of cardiovascular disease. The functional and signaling pathways that are involved in IGF-1 modulation of platelet function, however, are presently unknown. Here, I report that IGF-1 stimulation of platelets results in dose-dependent phosphorylation of the IGF receptor in the range of 1 to 100 nM. Phosphorylation of the IGF receptor is rapid and sustained, with maximal phosphorylation reached within 1 minute. Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). IGF-1-stimulated tyrosine phosphorylation of IRS-1 and IRS-2 and subsequent p85 binding is transient and precedes phosphorylation of protein kinase B (PKB) on Ser473. PAR-1-mediated platelet aggregation is potentiated by IGF-1 and this potentiation, together with PKB phosphorylation, is abolished by the PI3K alpha inhibitors PI-103 and PIK-75. Importantly, the IGF receptor inhibitor NVP-AEW541 and the neutralization antibody alpha IR3 inhibit SFLLRN-stimulated aggregation, implicating IGF-1 in autocrine regulation of platelet function. These results demonstrate that IGF-1 activates the IGF receptor/IRS/PI3K/PKB pathway, and that PI3Ka, is essential for the potentiatory effect of IGF-1 on platelet responses.