The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a banier-protective response in endothelial cells
The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a banier-protective response in endothelial cells
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DOI：
10.1182/blood-2007-06-096651
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发表时间：
2007-12-01
期刊：
影响因子：
20.3
通讯作者：
Rezaie, Alireza R.
中科院分区：
文献类型：
--
作者：
Bae, Jong-Sup;Yang, Likui;Rezaie, Alireza R.
最近的研究表明，活化蛋白C（APC）可能通过内皮蛋白C受体（EPCR）依赖性切割血管内皮细胞上的蛋白酶激活受体1（PAR-1）发挥其细胞保护和抗炎活性。注意到（1）内皮细胞上的蛋白C的活化需要凝血酶，（2）相对于APC，凝血酶以高约3至4个数量级的催化效率切割PAR-1，和（3）PAR-1是凝血酶的促炎活性的靶标，不理解当凝血酶存在时APC如何能够通过PAR-1的切割引发保护性信号传导应答。在这项研究中，我们证明了EPCR与内皮细胞脂筏中的小窝蛋白1相关，并且其被蛋白C/APC的γ-羧基谷氨酸（Gla）结构域占据导致其与小窝蛋白1解离，并通过PAR-1与百日咳毒素敏感的G（i）-蛋白偶联将PAR-1募集到保护性信号通路。因此，当EPCR与蛋白C结合时，内皮细胞中的PAR-1切割依赖性保护性信号传导反应可以由凝血酶或APC介导。这些结果为理解PAR-1和EPCR如何参与内皮细胞的保护性信号事件提供了一个新的范例。
Recent studies have indicated that activated protein C (APC) may exert its cytoprotective and anti-inflammatory activities through the endothelial protein C receptor (EPCR)-dependent cleavage of protease-activated receptor 1 (PAR-1) on vascular endothelial cells. Noting that (1) the activation of protein C on endothelial cells requires thrombin, (2) relative to APC, thrombin cleaves PAR-1 with approximately 3 to 4 orders of magnitude higher catalytic efficiency, and (3) PAR-1 is a target for the proinflammatory activity of thrombin, it is not understood how APC can elicit a protective signaling response through the cleavage of PAR-1 when thrombin is present. In this study, we demonstrate that EPCR is associated with caveolin-1 in lipid rafts of endothelial cells and that its occupancy by they-carboxyglutamic acid (Gla) domain of protein C/APC leads to its dissociation from caveolin-1 and recruitment of PAR-1 to a protective signaling pathway through cou-pling of PAR-1 to the pertussis toxin-sensitive G(i)-protein. Thus, when EPCR is bound by protein C, the PAR-1 cleavage-dependent protective signaling responses in endothelial cells can be mediated by either thrombin or APC. These results provide a new paradigm for understanding how PAR-1 and EPCR participate in protective signaling events in endothelial cells.