The Protease‐activated Receptors and Their Cellular Expression and Function in Blood‐related Cells

Hou,; Howells,; Kapas,; Macey,

doi:10.1046/j.1365-2141.1998.00696.x

Cited by 62 publications

(42 citation statements)

References 61 publications

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“…Thrombin-mediated activation of cell-surface receptors, including those on endothelial cells, is pleiotropic and results in: increased cytosolic Ca 2+ , stimulation of various second messenger systems, kinase activation, induction of mitosis, and the flux of ions in and out of the cell (Bartha et al, 1989;Brock and Capasso, 1989;Garcia et al, 1995;Magazine et al, 1996;Molino et al, 1997;Pollock et al, 1988;Schini et al, 1989;Sugama and Malik, 1992;Tesfamariam et al, 1993). Thrombin receptors belong to the protease-activated receptor (PAR) family of seven-transmembrane-domain, G-protein-linked, cell-surface receptors (reviewed by Brass and Molino, 1997;Hou et al, 1998;Jamieson, 1997). To date, three members of the PAR family, PAR-1 (Rasmussen et al, 1991;Vu et al, 1991), PAR-3 (Ishihara et al, 1997) and PAR-4 (Kahn et al, 1998), have been identified as thrombin sensitive.…”

Section: Introductionmentioning

confidence: 99%

Thrombin induces endothelial cell-surface exposure of the plasminogen receptor annexin 2

Peterson

Sutherland

Nesheim

et al. 2003

Journal of Cell Science

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Cell-surface annexin 2 (A2) and its ligand p11 have been implicated in fibrinolysis because of their ability to accelerate tissue plasminogen activator (tPA)-mediated activation of plasminogen to plasmin. Because thrombin is a potent cell modulator obligately produced at the site of clot formation, we hypothesized that the amount of cell-surface A2 and p11 might be altered by thrombin with consequent effects on plasmin generation. In support of this hypothesis, immunofluorescence microscopy and hydrophilic biotinylation experiments showed that both A2 and p11 were significantly increased on the surface of human umbilical vein endothelial cells (HUVECs)treated with thrombin (0.8-8 nM) for 5 minutes followed by 1 hour at 37°C. Intracellular immunofluorescence microscopy and immunoblot analyses of whole cell extracts revealed increased p11 but unchanged A2 in response to thrombin,suggesting that transbilayer trafficking of A2 might be controlled by p11. The thrombin receptor-activating peptide (TRAP) similarly affected cells,demonstrating that cell signaling at least involved the type-1 protease activated receptor (PAR-1). An effect on the fibrinolysis pathway after treatment of HUVECs with thrombin was shown by increased fluorescein-labeled plasminogen binding to cells, which was inhibited by an antibody specific for p11. This was confirmed by observing that thrombin pretreatment of HUVECs increased biotin-modified plasminogen binding. Utilizing a chromogenic assay,pretreatment of HUVECs by thrombin further enhanced activation of the Glu and Lys forms of plasminogen by tPA. These data suggest a novel mechanism that links the coagulation and fibrinolysis pathways by thrombin-mediated feedback.

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Section: Introductionmentioning

confidence: 99%

Thrombin induces endothelial cell-surface exposure of the plasminogen receptor annexin 2

Peterson

Sutherland

Nesheim

et al. 2003

Journal of Cell Science

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“…Thrombin-induced chemotaxis is well established in monocytes and vascular smooth muscle cells (1,2). Cell migration requires actin polymerization at the leading edge of the polarized cells and myosin activation at the rear, thereby enabling cell contraction and detachment (28).…”

Section: Figurementioning

confidence: 99%

“…When generated in close proximity to its cellular receptors (3,4), thrombin triggers not only increased fibrin deposition, but also activation of cells expressing protease-activated receptors (PARs), 4 which include endothelial and vascular smooth muscle cells as well as various blood cells (1,2,5).…”

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confidence: 99%

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Mature Dendritic Cells Express Functional Thrombin Receptors Triggering Chemotaxis and CCL18/Pulmonary and Activation-Regulated Chemokine Induction

Syrovets

Paskaš

et al. 2008

The Journal of Immunology

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Protease-activated receptors (PARs) are a family of G protein-coupled receptors that are activated by serine protease-mediated proteolytic cleavage of their extracellular domain. We have previously characterized the expression and function of PARs in human monocytes and macrophages, yet information about PARs in dendritic cells (DC) is scarce. Monocyte-derived immature DC do not express PARs. Upon maturation with LPS, but not with TNF-α or CD40 ligand, DC express PAR1 and PAR3, but not PAR2 or PAR4. Stimulation of DC with the serine protease thrombin or PAR1-activating peptide elicits actin polymerization and concentration-dependent chemotactic responses in LPS-, but not in TNF-α-matured DC. The thrombin-induced migration is a true chemotaxis with only negligible chemokinesis. Stimulation of PARs with thrombin or the respective receptor-activating peptides activates ERK1/2 and Rho kinase as well as subsequent phosphorylation of the regulatory myosin L chain 2. The ERK1/2- and Rho kinase 1-mediated phosphorylation of myosin L chain 2 was indispensable for the PAR-mediated chemotaxis as shown by pharmacological inhibitors. Additionally, thrombin stimulated the Rho-dependent release of the CC chemokine CCL18/pulmonary and activation-regulated chemokine, which induces chemotaxis of lymphocytes and immature DC as well as fibroblast proliferation. The colocalization of CD83+ DC with CCL18 in human atherosclerotic plaques revealed by immunofluorescence microscopy combined with the presence of functionally active thrombin receptors on mature DC point to a previously unrecognized functional role of thrombin in DC biology. The thrombin-induced stimulation of mature DC may be of particular relevance in atherosclerotic lesions, which harbor all components of this novel mechanism.

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“…Thrombin, FXa, the TF-FVIIa complex activate protease-activated receptors (protease-activated receptor family), which play a pivotal role in embryogenesis, vasculogenesis, angiogenesis and neuronal signalling. 49,50 Activated PC also interferes with protease-activated receptor activation through interaction with EPCR. 51 …”

Section: Ii-3-3-coagulation and Inflammationmentioning

confidence: 99%

From normal to pathological hemostasis

Lasne

Jude

Susen

2006

Can J Anesth/J Can Anesth

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Purpose:To review the evolution of knowledge on physiological hemostasis and the main abnormalities that may interfere with hemostasis in the perioperative period.Methods: Narrative review of the literature, including relevant papers published in English.Principal findings: Physiological hemostasis controls blood fluidity and rapidly induces hemostatic plug formation in order to stop or limit bleeding. The three distinct phases of the hemostatic process, primary hemostasis, coagulation and fibrinolysis are closely linked to each other and precisely regulated in order to efficiently close vessel wounds, promote vascular healing and maintain vessel patency. Primary hemostasis is the result of complex interactions between the vascular wall, platelets and adhesive proteins. Initiation of the coagulation pathway in vivo is secondary to the exposure of tissue factor (TF) and the formation of TF/VIIa complex which can activate both FIX and FX. This initiation phase is followed by a propagation phase with amplification of thrombin generation. Several control mechanisms exist for localizing fibrin formation to the site of injury including tissue factor pathway inhibitor, protein C system, antithrombin, and glycosaminoglycans on the vessel wall. Fibrinolysis is also a highly regulated system that controls fibrin dissolution. Both constitutive and acquired hemostasic defects exist. The consequences of these abnormalities are highly variable according to the type of defect, and to the genetic and environmental background. Conclusion:Hemostasis is one of the most complex physiological self-defence systems, not only involved in control of blood fluidity but also interfering in major physiopathological processes. The evolution of our knowledge of the physiology of hemostasis has numerous implications for therapy. P HYSIOLOGICAL hemostasis is a highly adaptative process that controls blood fluidity, and rapidly induces hemostatic plug formation after vascular injury, in order to stop or limit bleeding. After an initial triggering event, sequential steps occur, including a complex cascade of clotting factor and platelet activation. Red blood cells, leukocytes and endothelial cells are also involved in the propagation and the regulation of clot formation. The three distinct phases of the hemostatic process are pri- From normal to pathological hemostasis [De l'hémostase normale à l'hémostase pathologique] Objectif

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The Protease‐activated Receptors and Their Cellular Expression and Function in Blood‐related Cells

Cited by 62 publications

References 61 publications

Thrombin induces endothelial cell-surface exposure of the plasminogen receptor annexin 2

Thrombin induces endothelial cell-surface exposure of the plasminogen receptor annexin 2

Mature Dendritic Cells Express Functional Thrombin Receptors Triggering Chemotaxis and CCL18/Pulmonary and Activation-Regulated Chemokine Induction

From normal to pathological hemostasis

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