The Pleiotropic Effects of Tissue Factor: a Possible Role for Factor VIIa-induced Intracellular Signalling? | Semantic Scholar (2024)

It is now understood that the role of TF in angiogenesis is both coagulation-dependent and independent and the recent evidence for this emerging insight will be the subject of this review.

p21Ras activation is instrumental in F VIIa signal transduction and the FVIIa‐dependent activation of p 21Ras involves either PKC or Src‐dependent mechanisms, depending on the cell type investigated.

This review relates the current understanding of direct TF signaling pathways to the emerging roles of TF in (patho)physiology to show the importance of direct or indirect cell signaling in inflammation, tumor growth, and angiogenesis.

The role of TF and its ligand FVIIa in inflammation, sepsis, and signal transduction is discussed, and the way in which these processes interact is described.

The molecular elucidation of the role of these coagulation factors in cancer-associated thrombosis and metastatic progression has not been understood till date.

It is proposed that FVIIa-induced cell survival may explain why overexpression of TF is associated with successful metastasis.

The results show that the sequence hom*ology between the cytokine class II receptors and TF is reflected in similar downstream signal transduction and the activation of STAT transcription factors provides an obvious link between FVIIa:TF and the associated pro-inflammatory events.

It is observed that in both BHK and HaCaT cells FVIIa-induced MAP kinase activation correlates with p21Ras activation, and that this p21 ras activation is essential for F VIIa- induced MAP kinases activation.

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The features of TF structure and function which tailor it to the role of initiator of the coagulation cascade are considered and a kinetic model for the molecular mechanism of TF-initiated clotting is reviewed.

The features of TF structure and function which tailor it to the role of initiator of the coagulation cascade are considered and a kinetic model for the molecular mechanism of TF-initiated clotting is reviewed.

Evidence is reported suggesting that protease-activated receptor 2 or a close hom*ologue may be a necessary but not sufficient component of this particular signal transduction pathway in coagulation factors VIIa and Xa.

These studies provide the first demonstration of a direct proinflammatory role for TF acting as a cell-signaling receptor, and demonstrate that, in addition to its role in activation of coagulation, TF can directly augment macrophage activation.

It is reported that inactivation of the tissue factor gene (TF) results in abnormal circulation from yolk sac to embryo beyond embryonic day 8.5, leading to embryo wasting and death, implying that tissue factor has a role in bloodvessel development.

Alanine-scanning mutagenesis has identified tissue factor residues important for factor VIIa binding on the opposite side of the molecule compared to the growth hormone receptor, with the binding determinants residing on beta-strands rather than on loops.

The ocrystal structure of the extracellular region of tissue factor is determined and this is the first reported structure of a representative of the class 2 cytokine receptor family, which also includes interferon-α, interferons-γ and interleukin-10 receptors.

The data suggest that the intracellular response was not induced by an autocrine release of a soluble mediator to the medium, and is distinctly different from that induced by trypsin, thrombin and FXa not involving any of the known PARs.

It is reported that TF mRNA and protein are rapidly and markedly induced in early and late passaged vascular smooth muscle cells (VSMC) by growth factors, vasoactive agonists, and a clotting factor (alpha-thrombin) and the possibility that protein kinase C activation may not be necessary for TF mRNA induction in VSMC.

The properties of this rediscovered inhibitor appear, at least in part, to explain the clinical requirement for both the extrinsic and intrinsic pathways of the cascade and waterfall theories of blood clotting and have led to a reformulation of the coagulation mechanism.

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