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Tissue factor and cell activation Volume 7, issue 2, Mars - Avril 2001

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Service d'hématologie biologique et d'immunologie, hôpital Louis-Mourier, AP-HP, 178, rue des Renouillers, 92701 Colombes cedex.

Tissue factor is a transmembrane glycoprotein. When coupled to its ligand, activated factor VII, tissue factor is the main activator of coagulation. Formation of the tissue factor-factor VIIa complex activates coagulation cascades, leading to thrombin generation and fibrin formation. Activation of coagulation, an extracellular event, is not affected by deletion of the tissue factor cytoplasmic domain. Recent work has shown that tissue factor also has characteristics of a true receptor, namely a specific, high-affinity interaction with its ligand, emission of intracellular signals, and activation of cell functions. It rapidly emerged that multiple mechanisms govern this activation. In most cases, the rise in calcium fluxes, MAP kinase activation and gene transcription are independent of the tissue factor intracellular domain and of the thrombin and activated factor X activity generated downstream. Proteolytic activation of an unidentified receptor by factor VIIa is probably involved. Thrombin and activated factor X also trigger intracellular signals via their own receptors. Other events, such as adherence and migration of tissue factor-expressing cells and, according to some authors, VEGF expression by malignant cells, are independent of tissue factor-factor VIIa protease activity but dependent on the intracellular domain. Metastatic development after injection of malignant cells to SCID mice has served as a model to demonstrate the key role of both the tissue factor intracellular domain and proteolytic activity in the metastatic potential of tumor cells. The tissue factor-mediated activation of several transduction pathways and the expression of many genes points to its involvement in physiological processes such as wound healing and immune responses, and also in pathological settings such as inflammation and atherosclerosis. The ability of compounds coupled to inactivated F VIIa to counter such detrimental processes is currently being studied.