Tissue Factor–Factor VIIa Signaling

Abstract

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. Key Words: tissue factor Ⅲ factor VIIa Ⅲ protease activated receptors Ⅲ cell signaling T he close link between coagulation and various diseases, such as sepsis, atherosclerosis, and tumor metastasis, suggests a complex interplay between the clotting cascade and disease progression. Numerous studies have demonstrated that coagulation proteases can function like hormones to regulate cellular behavior. For example, thrombin, the principal protease generated during coagulation, has been shown to activate platelets and regulate the behavior of other cells by transmitting signals via activation of G proteincoupled protease activated receptors (PARs). Although there has been initial skepticism on whether other clotting proteases can also activate PARs, recent studies provide convincing evidence that many proteases involved in clotting can indeed activate PARs and regulate cellular behaviors at physiological concentrations. One such protease, FVIIa, the physiological initiator of the coagulation cascade, has received much attention lately. The focus of the present article is to review briefly recent developments in tissue factor (TF)-VIIa proteolytic activity-mediated cell signaling. TF-Factor VIIaTF is a transmembrane cellular receptor for FVII/FVIIa. Binding of plasma FVII/FVIIa to TF triggers the coagulation cascade, which leads to thrombin generation that subsequently stimulates platelet activation and cleaves fibrinogen. Under normal conditions, TF is constitutively expressed in many cell types, including fibroblasts and pericytes in and surrounding blood vessel walls, but is not expressed in blood cells or the endothelial cells that line blood vessels. 1,2 However, under certain pathological conditions, such as sepsis and cancer, monocytes 3 and endothelial cells 4 express TF, although the latter finding has not been confirmed by others. 5 Thus, blood vessel wall injury or certain disease conditions permit FVII/FVIIa interaction with TF on cell surfaces. The activation of TF-induced coagulation pathway not only leads to fibrin formation but also contributes to vascular remodeling, which is caused by growth factors secreted by ac...

MDA-9/Syntenin Is Essential for Factor VIIa-induced Signaling, Migration, and Metastasis in Melanoma Cells

“…A number of gain-and loss-of-function studies have shown that genetic modulation of TF promotes tumor cell invasion/migration and metastasis in vivo (20 -22). Current studies indicate that the ternary TF⅐FVIIa⅐Xa complex, efficiently signals through PAR-1 or PAR-2 in a FXa-dependent manner (23,24) and cross-talks with several important cellular signaling pathways, including MAPK pathway, Src family tyrosine kinases, and NFB members (25,26). Considering these many provocative findings, we have presently investigated the possible role of TF⅐FVIIa and the induced signaling pathways in regulation of MDA-9/syntenin expression.…”

Dérégulation de l’hémostase dans les infections à filovirus

“…Cette activation de la voie du facteur tissulaire -dite intrinsèque -conduit également à la consommation des plaquettes. De plus, le complexe FT-FVIIa est un élément de signalisation connu notamment pour induire dans les cellules un afflux de Ca 2+ ; c'est aussi un facteur pro-inflammatoire (via l'induction d'IL-6 et d'IL-8) [34]. Différentes protéines recombinantes (rNAPC2 et APC/Xigris) inhibitrices de la voie du facteur tissulaire ont montré leur efficacité dans le traitement de l'infection à virus Ebola chez le singe [35,36].…”

Factor VIIa Interaction With Tissue Factor and Endothelial Cell Protein C Receptor on Cell Surfaces

“…Binding of FVIIa to TF on cell surfaces not only triggers the coagulation cascade, but also induces intracellular signaling; however, the latter process depends on the availability of specific protease-activated receptors (PAR) on the cell surface, and on other cell-associated proteins near TF-FVIIa complexes on the cell membrane (13). Thus, not all cells that express TF are capable of transmitting cell signaling in response to FVIIa binding.…”