The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells

Recent studies have indicated that activated protein C (APC) may exert its cytoprotective and anti-inflammatory activities through the endothelial protein C receptor (EPCR)-dependent cleavage of protease-activated receptor 1 (PAR-1) on vascular endothelial cells. Noting that (1) the activation of pr...

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Vydané v:Blood Ročník 110; číslo 12; s. 3909
Hlavní autori: Bae, Jong-Sup, Yang, Likui, Manithody, Chandrashekhara, Rezaie, Alireza R
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 01.12.2007
Predmet:
Antigens, CD - metabolism
Caveolin 1 - metabolism
Cell Line
Cell Membrane Permeability - drug effects
Endothelial Cells - metabolism
Endothelial Cells - pathology
Endothelial Protein C Receptor
GTP-Binding Protein alpha Subunits, Gi-Go - metabolism
Hemostatics - metabolism
Hemostatics - pharmacology
Humans
Inflammation - metabolism
Inflammation - pathology
Ligands
Membrane Microdomains - metabolism
Membrane Microdomains - pathology
Protein C - metabolism
Protein C - pharmacology
Receptor, PAR-1 - metabolism
Receptors, Cell Surface - metabolism
Recombinant Proteins - metabolism
Recombinant Proteins - pharmacology
Signal Transduction - drug effects
Thrombin - metabolism
Thrombin - pharmacology
ISSN:0006-4971
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Shrnutí:Recent studies have indicated that activated protein C (APC) may exert its cytoprotective and anti-inflammatory activities through the endothelial protein C receptor (EPCR)-dependent cleavage of protease-activated receptor 1 (PAR-1) on vascular endothelial cells. Noting that (1) the activation of protein C on endothelial cells requires thrombin, (2) relative to APC, thrombin cleaves PAR-1 with approximately 3 to 4 orders of magnitude higher catalytic efficiency, and (3) 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 gamma-carboxyglutamic acid (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 G(i)-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 protective signaling events in endothelial cells.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0006-4971
DOI:10.1182/blood-2007-06-096651