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Disulfide isomerization switches tissue factor from coagulation to cell signaling
- Source :
- Proceedings of the National Academy of Sciences of the United States. Sept 19, 2006, Vol. 103 Issue 38, p13932, 6 p.
- Publication Year :
- 2006
-
Abstract
- Cell-surface tissue factor (TF) binds the serine protease factor Vlla to activate coagulation or, alternatively, to trigger signaling through the G protein-coupled, protease-activated receptor 2 (PAR2) relevant to inflammation and angiogenesis. Here we demonstrate that TF*Vlla-mediated coagulation and cell signaling involve distinct cellular pools of TF. The surface-accessible, extracellular [Cys.sup.186]-[Cys.sup.209] disulfide bond of TF is critical for coagulation, and protein disulfide isomerase (PDI) disables coagulation by targeting this disulfide. A TF mutant (TF C209A) with an unpaired [Cys.sup.186] retains TF*Vlla signaling activity, and it has reduced affinity for Vlla, a characteristic of signaling TF on cells with constitutive TF expression. We further show that PDI suppresses TF coagulant activity in a nitric oxide-dependent pathway, linking the regulation of TF thrombogenicity to oxidative stress in the vasculature. Furthermore, a unique monoclonal antibody recognizes only the noncoagulant, cryptic conformation of TF. This antibody inhibits formation of the TF-PAR2 complex and TF.Vlla signaling, but it does not prevent coagulation activation. These experiments delineate an upstream regulatory mechanism that controls TF function, and they provide initial evidence that TF*Vlla signaling can be specifically inhibited with minimal effects on coagulation.
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 103
- Issue :
- 38
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.153240589