Eg. Fischer et al., Tumor cell adhesion and migration supported by interaction of a receptor-protease complex with its inhibitor, J CLIN INV, 104(9), 1999, pp. 1213-1221
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
.