title: Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor.
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.
authors.affiliation: Department of Pathology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: E G
authors.initials: EG
authors.lastname: Fischer
authors.forename: M
authors.initials: M
authors.lastname: Riewald
authors.forename: H Y
authors.initials: HY
authors.lastname: Huang
authors.forename: Y
authors.initials: Y
authors.lastname: Miyagi
authors.forename: Y
authors.initials: Y
authors.lastname: Kubota
authors.forename: B M
authors.initials: BM
authors.lastname: Mueller
authors.forename: W
authors.initials: W
authors.lastname: Ruf
mesh_terms: D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D015942:Factor VIIa / Q000378:metabolism; D005353:Fibronectins / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008074:Lipoproteins / Q000378:metabolism / Q000494:pharmacology; D009363:Neoplasm Proteins; D011257:Pregnancy Proteins / Q000378:metabolism; D015398:Signal Transduction; D013925:Thromboplastin / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D005353:Fibronectins; D006023:Glycoproteins; D008074:Lipoproteins; D009363:Neoplasm Proteins; D011257:Pregnancy Proteins; C051928:lipoprotein-associated coagulation inhibitor; C021240:tissue-factor-pathway inhibitor 2; D006493:Heparin; D013925:Thromboplastin; D010450:Endopeptidases; D015942:Factor VIIa; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant