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???displayArticle.abstract??? Protease-activated receptor 2 (PAR2) is expressed by vascular endothelial cells and other cells in which its function and physiological activator(s) are unknown. Unlike PAR1, PAR3, and PAR4, PAR2 is not activatable by thrombin. Coagulation factors VIIa (FVIIa) and Xa (FXa) are proteases that act upstream of thrombin in the coagulation cascade and require cofactors to interact with their substrates. These proteases elicit cellular responses, but their receptor(s) have not been identified. We asked whether FVIIa and FXa might activate PARs if presented by their cofactors. Co-expression of tissue factor (TF), the cellular cofactor for FVIIa, together with PAR1, PAR2, PAR3, or PAR4 conferred TF-dependent FVIIa activation of PAR2 and, to lesser degree, PAR1. Responses to FXa were also observed but were independent of exogenous cofactor. The TF/FVIIa complex converts the inactive zymogen Factor X (FX) to FXa. Strikingly, when FX was present, low picomolar concentrations of FVIIa caused robust signaling in cells expressing TF and PAR2. Responses in keratinocytes and cytokine-treated endothelial cells suggested that PAR2 may be activated directly by TF/FVIIa and indirectly by TF/FVIIa-generated FXa at naturally occurring expression levels of TF and PAR2. These results suggest that PAR2, although not activatable by thrombin, may nonetheless function as a sensor for coagulation proteases and contribute to endothelial activation in the setting of injury and inflammation. More generally, these findings highlight the potential importance of cofactors in regulating PAR function and specificity.
Bevilacqua,
Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1.
1986, Pubmed
Bevilacqua,
Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1.
1986,
Pubmed
Boukamp,
Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line.
1988,
Pubmed
Brozna,
Shwartzman reaction.
1990,
Pubmed
Camera,
Cooperation between VEGF and TNF-alpha is necessary for exposure of active tissue factor on the surface of human endothelial cells.
1999,
Pubmed
Camerer,
Coagulation factors VII and X induce Ca2+ oscillations in Madin-Darby canine kidney cells only when proteolytically active.
1996,
Pubmed
Camerer,
Coagulation factors VIIa and Xa induce cell signaling leading to up-regulation of the egr-1 gene.
1999,
Pubmed
Camerer,
Cell biology of tissue factor, the principal initiator of blood coagulation.
1996,
Pubmed
Chen,
Thrombin receptor activation. Confirmation of the intramolecular tethered liganding hypothesis and discovery of an alternative intermolecular liganding mode.
1994,
Pubmed
,
Xenbase
Coughlin,
How the protease thrombin talks to cells.
1999,
Pubmed
Damiano,
Increased expression of protease activated receptor-2 (PAR-2) in balloon-injured rat carotid artery.
1999,
Pubmed
D'Andrea,
Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues.
1998,
Pubmed
Denis,
A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis.
1998,
Pubmed
Drake,
Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis.
1989,
Pubmed
Esmon,
Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?
2000,
Pubmed
Han,
Isolation of a protein Z-dependent plasma protease inhibitor.
1998,
Pubmed
Hattori,
Stimulated secretion of endothelial von Willebrand factor is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein GMP-140.
1989,
Pubmed
Ishihara,
Protease-activated receptor 3 is a second thrombin receptor in humans.
1997,
Pubmed
Ishii,
Kinetics of thrombin receptor cleavage on intact cells. Relation to signaling.
1993,
Pubmed
Kahn,
Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin.
1999,
Pubmed
Kahn,
A dual thrombin receptor system for platelet activation.
1998,
Pubmed
,
Xenbase
Mann,
Biochemistry and physiology of blood coagulation.
1999,
Pubmed
Marmur,
Tissue factor is rapidly induced in arterial smooth muscle after balloon injury.
1993,
Pubmed
Molino,
Interactions of mast cell tryptase with thrombin receptors and PAR-2.
1997,
Pubmed
Morrissey,
Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation.
1993,
Pubmed
Nicholson,
Effector cell protease receptor-1 is a vascular receptor for coagulation factor Xa.
1996,
Pubmed
Nystedt,
The proteinase-activated receptor 2 is induced by inflammatory mediators in human endothelial cells. Comparison with the thrombin receptor.
1996,
Pubmed
Nystedt,
Molecular cloning of a potential proteinase activated receptor.
1994,
Pubmed
,
Xenbase
Ollivier,
Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII.
1998,
Pubmed
Papapetropoulos,
Hypotension and inflammatory cytokine gene expression triggered by factor Xa-nitric oxide signaling.
1998,
Pubmed
Poulsen,
Signal transduction via the mitogen-activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor.
1998,
Pubmed
Røttingen,
Binding of human factor VIIa to tissue factor induces cytosolic Ca2+ signals in J82 cells, transfected COS-1 cells, Madin-Darby canine kidney cells and in human endothelial cells induced to synthesize tissue factor.
1995,
Pubmed
Sakai,
Binding of human factors VII and VIIa to a human bladder carcinoma cell line (J82). Implications for the initiation of the extrinsic pathway of blood coagulation.
1989,
Pubmed
Santulli,
Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes.
1995,
Pubmed
Senden,
Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells.
1998,
Pubmed
Sørensen,
Factor VIIa-induced p44/42 mitogen-activated protein kinase activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain.
1999,
Pubmed
Sprecher,
Molecular cloning, expression, and partial characterization of a second human tissue-factor-pathway inhibitor.
1994,
Pubmed
Steinhoff,
Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism.
2000,
Pubmed
Subramaniam,
Defects in hemostasis in P-selectin-deficient mice.
1996,
Pubmed
Taniguchi,
Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer.
1998,
Pubmed
Trejo,
The cloned thrombin receptor is necessary and sufficient for activation of mitogen-activated protein kinase and mitogenesis in mouse lung fibroblasts. Loss of responses in fibroblasts from receptor knockout mice.
1996,
Pubmed
Vergnolle,
Proteinase-activated receptor-2-activating peptides induce leukocyte rolling, adhesion, and extravasation in vivo.
1999,
Pubmed
Vu,
Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation.
1991,
Pubmed
,
Xenbase
