Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 14, Pages 7742-7747Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.141126698
Keywords
-
Categories
Funding
- NHLBI NIH HHS [P01 HL016411, R01 HL048752, HL 16411, HL 48752] Funding Source: Medline
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available