Tissue factor-factor VIIa signaling

Abstract

How does tissue factor (TF), whose principle role is to support clotting factor VIIa (FVIIa) in triggering the coagulation cascade, affect various pathophysiological processes? One of the answers is that TF interaction with FVIIa not only initiates clotting but also induces cell signaling via activation of G-protein-coupled protease activated receptors (PARs). Recent studies using various cell model systems and limited in vivo systems are beginning to define how TF-VIIa-induced signaling regulates cellular behavior. Signaling pathways initiated by both TF-VIIa protease activation of PARs and phosphorylation of the TF-cytoplasmic domain appear to regulate cellular functions. In the present article, we review the emerging data on the mechanism of TF-mediated cell signaling and how it regulates various cellular responses, with particular focus on TF-VIIa protease-dependent signaling.

Figure 1

A schematic representation of TF–VIIa protease-induced signaling. TF–VIIa activates PAR2 and the ternary complex of TF–VIIa–Xa activates both PAR1 and PAR2. Activation of PAR2-specific signaling pathway may lead to phosphorylation of TF cytoplasmic tail. Phosphorylation of TF cytoplasmic domain releases its negative regulatory control of PAR2-mediated signaling.

Figure 2

A comparison of efficiency of TF–VIIa-mediated and TF–VIIa–Xa-mediated cell signaling. MDA-MB-231 cells were stimulated with varying concentrations of FVIIa in the presence or absence of substrate FX (175 nM). The signaling was evaluated in either IP3 hydrolysis assay (A) or IL-8 gene expression (B).

Figure 3

TF–VIIa signaling mediated cellular effects and their contribution to various pathophysiological processes (see text for details).

Figure 4

TF–VIIa signaling and angiogenesis. Binding of FVIIa to tumor cell TF activates a genetic program, which leads to upregulation of various chemokines, cytokines, and growth factors, including IL-8, CCN1, and VEGF. These secreted cytokines and growth factors from tumor cells promote endothelial cell proliferation and migration, leading to angiogenesis.