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The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors

Academic Article
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Overview

authors

  • Disse, J.
  • Petersen, H. H.
  • Larsen, K. S.
  • Persson, E.
  • Esmon, N.
  • Esmon, C. T.
  • Teyton, Luc
  • Petersen, L. C.
  • Ruf, Wolfram

publication date

  • February 2011

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Protease-activated receptor (PAR) signaling is closely linked to the cellular activation of the pro- and anticoagulant pathways. The endothelial protein C receptor (EPCR) is crucial for signaling by activated protein C through PAR1, but EPCR may have additional roles by interacting with the 4-carboxyglutamic acid domains of procoagulant coagulation factors VII (FVII) and X (FX). Here we show that soluble EPCR regulates the interaction of FX with human or mouse tissue factor (TF)-FVIIa complexes. Mutagenesis of the FVIIa 4-carboxyglutamic acid domain and dose titrations with FX showed that EPCR interacted primarily with FX to attenuate FX activation in lipid-free assay systems. In human cell models of TF signaling, antibody inhibition of EPCR selectively blocked PAR activation by the ternary TF-FVIIa-FXa complex but not by the non-coagulant TF-FVIIa binary complex. Heterologous expression of EPCR promoted PAR1 and PAR2 cleavage by FXa in the ternary complex but did not alter PAR2 cleavage by TF-FVIIa. In murine smooth muscle cells that constitutively express EPCR and TF, thrombin and FVIIa/FX but not FVIIa alone induced PAR1-dependent signaling. Although thrombin signaling was unchanged, cells with genetically reduced levels of EPCR no longer showed a signaling response to the ternary complex. These results demonstrate that EPCR interacts with the ternary TF coagulation initiation complex to enable PAR signaling and suggest that EPCR may play a role in regulating the biology of TF-expressing extravascular and vessel wall cells that are exposed to limited concentrations of FVIIa and FX provided by ectopic synthesis or vascular leakage.

subject areas

  • Animals
  • Antigens, CD
  • Cells, Cultured
  • Factor VIIa
  • Factor X
  • Glycoproteins
  • Humans
  • Mice
  • Mice, Knockout
  • Multienzyme Complexes
  • Myocytes, Smooth Muscle
  • Protein C
  • Protein Structure, Tertiary
  • Receptor, PAR-1
  • Receptor, PAR-2
  • Receptors, Cell Surface
  • Signal Transduction
  • Thrombin
  • Thromboplastin
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Identity

PubMed Central ID

  • PMC3037688

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M110.201228

PubMed ID

  • 21149441
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Additional Document Info

start page

  • 5756

end page

  • 5767

volume

  • 286

issue

  • 7

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