Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor

被引:269
作者
Riewald, M
Ruf, W [1 ]
机构
[1] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Vasc Biol, La Jolla, CA 92037 USA
关键词
D O I
10.1073/pnas.141126698
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The crucial role of cell signaling in hemostasis is clearly established by the action of the downstream coagulation protease thrombin that cleaves platelet-expressed C-protein-coupled protease activated receptors (PARs), Certain PARs are cleaved by the upstream coagulation proteases factor Xa (Xa) and the tissue factor (TF)factor VIIa (VIIa) complex, but these enzymes are required at high nonphysiological concentrations and show limited recognition specificity for the scissile bond of target PARs, However, defining a physiological mechanism of PAR activation by upstream proteases is highly relevant because of the potent anti-inflammatory in vivo effects of inhibitors of the TF initiation complex. Activation of substrate factor X (X) by the TF-VIIa complex is here shown to produce enhanced cell signaling in comparison to the TF-VIIa complex alone, free Xa, or Xa that is generated in situ by the intrinsic activation complex. Macromolecular assembly of X into a ternary complex of TF-VIIa-X is required for proteolytic conversion to Xa, and product Xa remains transiently associated in a TF-VIIa-Xa complex. By trapping this complex with a unique inhibitor that preserves Xa activity, we directly show that Xa in this ternary complex efficiently activates PAR-1 and -2, These experiments support the concept that proinflammatory upstream coagulation protease signaling is mechanistically coupled and thus an integrated part of the TF-VIIa-initiated coagulation pathway, rather than a late event during excessive activation of coagulation and systemic generation of proteolytic activity.
引用
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页码:7742 / 7747
页数:6
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