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

Tissue factor (TF), the cell-surface receptor for coagulation factor VIIa, supports metastasis. Equally important for this process are (a) interaction s of the TF cytoplasmic domain, which binds the mobility-enhancing actin-bi nding protein 280, and (b) the formation of a proteolytically active TF-VII a complex on the tumor cell surface. In primary bladder carcinoma cells, we fmd that this complex localizes to the invasive edge, in proximity to tumo r-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. Imm obilized heparin, a mimic for extracellular matrix-associated proteoglycans , binds physiological concentrations of TFPI-1 in a conformation that suppo rts TF-VIIa-dependent cell adhesion. Consistent with a functional role of T FPI-1 in complex extracellular matrices, we show that TF cooperates with in tegrin-mediated adhesion and migration on composite matrices that contain l igands for both integrins and the TF-VIIa complex. This study thus provides evidence for a novel mechanism of protease-supported migration that is ind ependent of proteolytic matrix degradation but rather involves protease-dep endent bridging of TF's extracellular domain to an ECM-associated inhibitor .