SEARCH:   Advanced

Blood, 1 December 2007, Vol. 110, No. 12, pp. 3909-3916. Prepublished online as a Blood First Edition Paper on September 6, 2007; DOI 10.1182/blood-2007-06-096651. This Article Full Text (PDF) All Versions of this Article: blood-2007-06-096651v1 110/12/3909    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 Bae, J.-S. Articles by Rezaie, A. R. Search for Related Content PubMed PubMed Citation Articles by Bae, J.-S. Articles by Rezaie, A. R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 19, 2007 Accepted August 23, 2007 The ligand occupancy of endothelial protein C receptor switches the PAR-1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells Jong-Sup Bae, Likui Yang, Chandrashekhara Manithody, and Alireza R. Rezaie* Edward A. Doisy Dept of Biochemistry & Molecular Biology, St. Louis University School of Medicine, St. Louis, MO, United States * Corresponding author; email: rezaiear{at}slu.edu. Recent studies have indicated that activated protein C (APC) may exert its cytoprotective and antiinflammatory activities through the endothelial protein C receptor (EPCR)-dependent cleavage of protease activated receptor 1 (PAR-1) on vascular endothelial cells. Noting that i) the activation of protein C on endothelial cells requires thrombin, ii) relative to APC, thrombin cleaves PAR-1 with ~3-4-orders of magnitude higher catalytic efficiency, and iii) 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 the Gla-domain of protein C/APC leads to its dissociation from caveolin-1 and recruitment of PAR-1 to a protective signaling pathway through coupling of PAR-1 to the pertussis toxin sensitive Gi-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 cytoprotective signaling events in endothelial cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. H. Finigan, A. Boueiz, E. Wilkinson, R. Damico, J. Skirball, H. H. Pae, M. Damarla, E. Hasan, D. B. Pearse, S. P. Reddy, et al. Activated protein C protects against ventilator-induced pulmonary capillary leak Am J Physiol Lung Cell Mol Physiol, June 1, 2009; 296(6): L1002 - L1011. [Abstract] [Full Text] [PDF] A. Russo, U. J. K. Soh, M. M. Paing, P. Arora, and J. Trejo Caveolae are required for protease-selective signaling by protease-activated receptor-1 PNAS, April 14, 2009; 106(15): 6393 - 6397. [Abstract] [Full Text] [PDF] M. Bezuhly, R. Cullen, C. T. Esmon, S. F. Morris, K. A. West, B. Johnston, and R. S. Liwski Role of activated protein C and its receptor in inhibition of tumor metastasis Blood, April 2, 2009; 113(14): 3371 - 3374. [Abstract] [Full Text] [PDF] A. Russo, U. J. K. Soh, and J. Trejo Proteases Display Biased Agonism at Protease-Activated Receptors: Location matters! Mol. Interv., April 1, 2009; 9(2): 87 - 96. [Abstract] [Full Text] [PDF] F. Niessen, C. Furlan-Freguia, J. A. Fernandez, L. O. Mosnier, F. J. Castellino, H. Weiler, H. Rosen, J. H. Griffin, and W. Ruf Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality Blood, March 19, 2009; 113(12): 2859 - 2866. [Abstract] [Full Text] [PDF] M. Tauseef, V. Kini, N. Knezevic, M. Brannan, R. Ramchandaran, H. Fyrst, J. Saba, S. M. Vogel, A. B. Malik, and D. Mehta Activation of Sphingosine Kinase-1 Reverses the Increase in Lung Vascular Permeability Through Sphingosine-1-Phosphate Receptor Signaling in Endothelial Cells Circ. Res., November 7, 2008; 103(10): 1164 - 1172. [Abstract] [Full Text] [PDF] L. J. Toltl, S. Beaudin, P. C. Liaw, and and the Canadian Critical Care Translational Biolo Activated Protein C Up-Regulates IL-10 and Inhibits Tissue Factor in Blood Monocytes J. Immunol., August 1, 2008; 181(3): 2165 - 2173. [Abstract] [Full Text] [PDF] R. A. Schuepbach, C. Feistritzer, L. F. Brass, and M. Riewald Activated protein C-cleaved protease activated receptor-1 is retained on the endothelial cell surface even in the presence of thrombin Blood, March 1, 2008; 111(5): 2667 - 2673. [Abstract] [Full Text] [PDF]

	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020