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Protease-activated receptor 2-dependent phosphorylation of the tissue factor cytoplasmic domain

Academic Article
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Overview

authors

  • Ahamed, J.
  • Ruf, Wolfram

publication date

  • May 2004

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Tissue factor (TF) is the physiological activator of the coagulation cascade that plays pathophysiological roles in metastasis, angiogenesis, and inflammation. Downstream in coagulation, thrombin is the central protease that signals through G protein-coupled, protease-activated receptors (PARs). However, the TF-VIIa-Xa complex upstream in coagulation also activates PAR1 and 2. Here, we address the question of whether signaling of the TF initiation complex is a relevant pathway that leads to TF cytoplasmic domain phosphorylation. In heterologous expression systems and primary endothelial cells, we demonstrate that the ternary TF-VIIa-Xa complex induces TF phosphorylation specifically by activating PAR2 but not through PAR1 signaling. In addition, TF cytoplasmic domain phosphorylation is induced only by TF-dependent signaling but not by other coagulation factors in endothelial cells. Phosphorylation of the Pro-directed kinase target site Ser258 is dependent on prior phosphorylation of Ser253 by protein kinase C (PKC) alpha. TF phosphorylation is somewhat delayed and coincides with sustained PKCalpha activation downstream of PAR2 but not PAR1 signaling. Phosphatidylcholine-dependent phospholipase C is the major pathway that leads to prolonged PKCalpha recruitment downstream of PAR2. Thus, PAR2 signaling specifically phosphorylates TF in a receptor cross-talk that distinguishes upstream from downstream coagulation protease signaling.

subject areas

  • Humans
  • Phosphorylation
  • Protein Structure, Tertiary
  • Receptor Cross-Talk
  • Receptor, PAR-2
  • Signal Transduction
  • Thromboplastin
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M401376200

PubMed ID

  • 15039423
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Additional Document Info

start page

  • 23038

end page

  • 23044

volume

  • 279

issue

  • 22

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