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Science 296 (5574): 1880-1882

Copyright © 2002 by the American Association for the Advancement of Science

Activation of Endothelial Cell Protease Activated Receptor 1 by the Protein C Pathway

Matthias Riewald,1 Ramona J. Petrovan,1 Aaron Donner,1 Barbara M. Mueller,2 Wolfram Ruf1*

The coagulant and inflammatory exacerbation in sepsis is counterbalanced by the protective protein C (PC) pathway. Activated PC (APC) was shown to use the endothelial cell PC receptor (EPCR) as a coreceptor for cleavage of protease activated receptor 1 (PAR1) on endothelial cells. Gene profiling demonstrated that PAR1 signaling could account for all APC-induced protective genes, including the immunomodulatory monocyte chemoattractant protein-1 (MCP-1), which was selectively induced by activation of PAR1, but not PAR2. Thus, the prototypical thrombin receptor is the target for EPCR-dependent APC signaling, suggesting a role for this receptor cascade in protection from sepsis.

1 Department of Immunology, C204, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Division of Cancer Biology, La Jolla Institute for Molecular Medicine, 4570 Executive Drive, San Diego, CA 92121, USA.
*   To whom correspondence should be addressed. E-mail: ruf{at}scripps.edu



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J. Biol. Chem. 282, 9251-9259
   Abstract »    Full Text »    PDF »
Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer.
P. Arora, T. K. Ricks, and J. Trejo (2007)
J. Cell Sci. 120, 921-928
   Abstract »    Full Text »    PDF »
Protease-Activated Receptor-1 (hPar1), A Survival Factor Eliciting Tumor Progression.
Z. Salah, M. Maoz, E. Pokroy, M. Lotem, R. Bar-Shavit, and B. Uziely (2007)
Mol. Cancer Res. 5, 229-240
   Abstract »    Full Text »    PDF »
Role of Protein C in Renal Dysfunction after Polymicrobial Sepsis.
A. Gupta, D. T. Berg, B. Gerlitz, G. R. Sharma, S. Syed, M. A. Richardson, G. Sandusky, J. G. Heuer, E. J. Galbreath, and B. W. Grinnell (2007)
J. Am. Soc. Nephrol. 18, 860-867
   Abstract »    Full Text »    PDF »
Plasmin(ogen) Promotes Renal Interstitial Fibrosis by Promoting Epithelial-to-Mesenchymal Transition: Role of Plasmin-Activated Signals.
G. Zhang, K. A. Kernan, S. J. Collins, X. Cai, J. M. Lopez-Guisa, J. L. Degen, Y. Shvil, and A. A. Eddy (2007)
J. Am. Soc. Nephrol. 18, 846-859
   Abstract »    Full Text »    PDF »
Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo.
T. Nishimura, T. Myles, A. M. Piliposky, P. N. Kao, G. J. Berry, and L. L. K. Leung (2007)
Blood 109, 1992-1997
   Abstract »    Full Text »    PDF »
Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells.
J.-S. Bae, L. Yang, and A. R. Rezaie (2007)
PNAS 104, 2867-2872
   Abstract »    Full Text »    PDF »
Endothelial Cell Protein C Receptor: Role Beyond Endothelium?.
M. Thiyagarajan, T. Cheng, and B. V. Zlokovic (2007)
Circ. Res. 100, 155-157
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Human Vascular Smooth Muscle Cells Express Functionally Active Endothelial Cell Protein C Receptor.
E. Bretschneider, B. Uzonyi, A.-A. Weber, J. W. Fischer, R. Pape, K. Lotzer, and K. Schror (2007)
Circ. Res. 100, 255-262
   Abstract »    Full Text »    PDF »
Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice.
X. Zheng, W. Li, J.-M. Gu, D. Qu, G. L. Ferrell, N. L. Esmon, and C. T. Esmon (2007)
Blood 109, 1003-1009
   Abstract »    Full Text »    PDF »
The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology.
K. Hirano (2007)
Arterioscler Thromb Vasc Biol 27, 27-36
   Abstract »    Full Text »    PDF »
The Rewards of Nicotine: Regulation by Tissue Plasminogen Activator-Plasmin System through Protease Activated Receptor-1..
T. Nagai, M. Ito, N. Nakamichi, H. Mizoguchi, H. Kamei, A. Fukakusa, T. Nabeshima, K. Takuma, and K. Yamada (2006)
J. Neurosci. 26, 12374-12383
   Abstract »    Full Text »    PDF »
Multifunctional Specificity of the Protein C/Activated Protein C Gla Domain.
R. J. S. Preston, E. Ajzner, C. Razzari, S. Karageorgi, S. Dua, B. Dahlback, and D. A. Lane (2006)
J. Biol. Chem. 281, 28850-28857
   Abstract »    Full Text »    PDF »
Protease-Activated Receptors in Cardiovascular Diseases.
A. J. Leger, L. Covic, and A. Kuliopulos (2006)
Circulation 114, 1070-1077
   Abstract »    Full Text »    PDF »
Modulation of Monocyte Function by Activated Protein C, a Natural Anticoagulant.
D. A. Stephenson, L. J. Toltl, S. Beaudin, and P. C. Liaw (2006)
J. Immunol. 177, 2115-2122
   Abstract »    Full Text »    PDF »
Role of a 5'-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene.
L. R. Mollica, J. T. B. Crawley, K. Liu, J. B. Rance, P. N. Cockerill, G. A. Follows, J.-R. Landry, D. J. Wells, and D. A. Lane (2006)
Blood 108, 1251-1259
   Abstract »    Full Text »    PDF »
Protective Signaling by Activated Protein C Is Mechanistically Linked to Protein C Activation on Endothelial Cells.
C. Feistritzer, R. A. Schuepbach, L. O. Mosnier, L. A. Bush, E. Di Cera, J. H. Griffin, and M. Riewald (2006)
J. Biol. Chem. 281, 20077-20084
   Abstract »    Full Text »    PDF »
Blockade of Angiogenesis by Small Molecule Antagonists to Protease-Activated Receptor-1: Association with Endothelial Cell Growth Suppression and Induction of Apoptosis.
P. Zania, S. Kritikou, C. S. Flordellis, M. E. Maragoudakis, and N. E. Tsopanoglou (2006)
J. Pharmacol. Exp. Ther. 318, 246-254
   Abstract »    Full Text »    PDF »
Plasminogen inhibits TNF{alpha}-induced apoptosis in monocytes.
J. W. Mitchell, N. Baik, F. J. Castellino, and L. A. Miles (2006)
Blood 107, 4383-4390
   Abstract »    Full Text »    PDF »

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