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Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor

Academic Article
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Overview

authors

  • Fischer, E. G.
  • Riewald, Matthias
  • Huang, H. Y.
  • Miyagi, Y.
  • Kubota, Y.
  • Mueller, B. M.
  • Ruf, Wolfram

publication date

  • November 1999

journal

  • Journal of Clinical Investigation  Journal

abstract

  • Tissue factor (TF), the cell-surface receptor for coagulation factor VIIa, supports metastasis. Equally important for this process are (a) interactions of the TF cytoplasmic domain, which binds the mobility-enhancing actin-binding protein 280, and (b) the formation of a proteolytically active TF-VIIa complex on the tumor cell surface. In primary bladder carcinoma cells, we find that this complex localizes to the invasive edge, in proximity to tumor-infiltrating vessels that stain intensely for TF pathway inhibitor (TFPI-1), the major inhibitor of the protease activity of the complex. In culture, binding of VIIa to TF-expressing tumor cells is sufficient to allow cell adhesion, migration, and intracellular signaling on immobilized TFPI-1. Immobilized heparin, a mimic for extracellular matrix-associated proteoglycans, binds physiological concentrations of TFPI-1 in a conformation that supports TF-VIIa-dependent cell adhesion. Consistent with a functional role of TFPI-1 in complex extracellular matrices, we show that TF cooperates with integrin-mediated adhesion and migration on composite matrices that contain ligands for both integrins and the TF-VIIa complex. This study thus provides evidence for a novel mechanism of protease-supported migration that is independent of proteolytic matrix degradation but rather involves protease-dependent bridging of TF's extracellular domain to an ECM-associated inhibitor.

subject areas

  • Carcinoma
  • Cell Adhesion
  • Cell Movement
  • Cysteine Endopeptidases
  • Dose-Response Relationship, Drug
  • Endopeptidases
  • Epithelium
  • Factor VIIa
  • Fibronectins
  • Glycoproteins
  • Heparin
  • Humans
  • Immunohistochemistry
  • Lipoproteins
  • Neoplasm Proteins
  • Pregnancy Proteins
  • Signal Transduction
  • Thromboplastin
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms
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Identity

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci7750

PubMed ID

  • 10545520
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Additional Document Info

start page

  • 1213

end page

  • 1221

volume

  • 104

issue

  • 9

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