Essential Role of Protein Kinase Cδ in Platelet Signaling, αIIbβ3 Activation, and Thromboxane A2 Release*
Essential Role of Protein Kinase Cδ in Platelet Signaling, αIIbβ3 Activation, and Thromboxane A2 Release*
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DOI：
10.1074/jbc.m604504200
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发表时间：
2006-08
影响因子：
4.8
通讯作者：
Daniel Yacoub;J. Théorêt;L. Villeneuve;Haissam Abou-Saleh;W. Mourad;B. Allen;Y. Merhi
中科院分区：
文献类型：
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作者：
Daniel Yacoub;J. Théorêt;L. Villeneuve;Haissam Abou-Saleh;W. Mourad;B. Allen;Y. Merhi
蛋白激酶C（PKC）家族是血小板活化和聚集中的重要信号介质。然而，主要的血小板PKC亚型及其下游效应物在血小板信号传导和功能中的相对重要性仍不清楚。使用分离的人血小板，我们报告了PKCδ，而不是PKCα或PKCβ，是胶原诱导的磷脂酶C依赖性信号传导、αIIbβ3活化和血小板聚集所必需的。对PKCδ磷酸化和在胶原蛋白和凝血酶激活后转运至膜的分析表明，它受到αIIbβ3由外向内信号传导的正调控。此外，PKCδ触发丝裂原活化蛋白激酶-激酶（MEK）/细胞外信号调节激酶（ERK）和p38 MAPK信号传导的活化。这导致随后释放血栓烷A2，其对于胶原诱导的而不是凝血酶诱导的血小板活化和聚集是必需的。这项研究为PKC在血小板功能中的作用提供了新的见解，其中PKCδ信号传导通过MEK/ERK和p38 MAPK途径是血栓素A2分泌所必需的。
The protein kinase C (PKC) family is an essential signaling mediator in platelet activation and aggregation. However, the relative importance of the major platelet PKC isoforms and their downstream effectors in platelet signaling and function remain unclear. Using isolated human platelets, we report that PKCδ, but not PKCα or PKCβ, is required for collagen-induced phospholipase C-dependent signaling, activation of αIIbβ3, and platelet aggregation. Analysis of PKCδ phosphorylation and translocation to the membrane following activation by both collagen and thrombin indicates that it is positively regulated by αIIbβ3 outside-in signaling. Moreover, PKCδ triggers activation of the mitogen-activated protein kinase-kinase (MEK)/extracellular-signal regulated kinase (ERK) and the p38 MAPK signaling. This leads to the subsequent release of thromboxane A2, which is essential for collagen-induced but not thrombin-induced platelet activation and aggregation. This study adds new insight to the role of PKCs in platelet function, where PKCδ signaling, via the MEK/ERK and p38 MAPK pathways, is required for the secretion of thromboxane A2.