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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2384-2391. Prepublished online as a Blood First Edition Paper on November 18, 2004; DOI 10.1182/blood-2004-09-3422. This Article Full Text (PDF) All Versions of this Article: 2004-09-3422v1 105/6/2384    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ahamed, J. Articles by Ruf, W. Search for Related Content PubMed PubMed Citation Articles by Ahamed, J. Articles by Ruf, W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 3, 2004 Accepted November 12, 2004 Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor-1 Jasimuddin Ahamed, Mattias Belting, and Wolfram Ruf* Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA * Corresponding author; email: ruf{at}scripps.edu. Tissue factor (TF) triggers upstream coagulation signaling via the activation of protease activated receptors (PARs) of relevance for inflammation and angiogenesis. TF pathway inhibitor-1 (TFPI-1) is the physiological inhibitor of TF-initiated coagulation, but its role in regulating TF signaling is poorly understood. Here, we demonstrate that endogenous, endothelial cell-expressed TFPI-1 controls TF-mediated signaling through PARs. In endothelial cells transduced with TF to mimic exacerbated TF expression in vascular cells, TF-VIIa-Xa ternary complex-dependent activation of PAR1 remained intact when TF-mediated Xa generation was blocked with 2.5-5 nM recombinant TFPI-1 (rTFPI-1). Concordantly, inhibition of signaling in PAR1-expressing CHO cells required ~30-fold higher rTFPI-1 concentrations than necessary for anticoagulation. Studies with proteoglycan-deficient CHO cells document a crucial role of accessory receptors in supporting rTFPI-1's anticoagulant and anti-signaling activities. Co-expression of PAR2 with TF enhanced rTFPI-mediated inhibition of TF-VIIa-Xa-mediated PAR1 signaling, suggesting an unexpected role of PAR2 in the inhibitory control of TF signaling. These experiments are of potential significance for the limited therapeutic benefit of rTFPI-1 in systemic inflammation and recommend caution to use anticoagulant potency as a measure to predict how efficacious TF-directed inhibitors block cell signaling during initiation of coagulation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Pan, T. A. White, T. A. Witt, A. Chiriac, C. S. Mueske, and R. D. Simari Vascular-Directed Tissue Factor Pathway Inhibitor Overexpression Regulates Plasma Cholesterol and Reduces Atherosclerotic Plaque Development Circ. Res., September 25, 2009; 105(7): 713 - 720. [Abstract] [Full Text] [PDF] G. Bhattacharjee, J. Ahamed, R. Pawlinski, C. Liu, N. Mackman, W. Ruf, and T. S. Edgington Factor Xa Binding to Annexin 2 Mediates Signal Transduction via Protease-Activated Receptor 1 Circ. Res., February 29, 2008; 102(4): 457 - 464. [Abstract] [Full Text] [PDF] J. Ahamed, H. H. Versteeg, M. Kerver, V. M. Chen, B. M. Mueller, P. J. Hogg, and W. Ruf Disulfide isomerization switches tissue factor from coagulation to cell signaling PNAS, September 19, 2006; 103(38): 13932 - 13937. [Abstract] [Full Text] [PDF] T. M. Hackeng, K. M. Sere, G. Tans, and J. Rosing Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor PNAS, February 28, 2006; 103(9): 3106 - 3111. [Abstract] [Full Text] [PDF]

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