2007 Sol Sherry Distinguished Lecture in Thrombosis—Cell Signaling of the TF Coagulation Pathway
Initiation of coagulation by the complex of tissue factor (TF) with its ligand coagulation factor VIIa is crucial for normal hemostasis, wound repair, and acute thrombotic complications of cardiovascular disease. Coagulation is coupled at multiple levels to cell signaling events through protease-mediated cleavage of the G-protein– coupled, protease-activated receptors (PARs). Diverse effects of thrombin-mediated PAR activation govern several aspects of physiology and pathology. However, the TF-VIIa complex can operate as a signaling complex without triggering downstream coagulation. On the one hand, nascent product Xa in the ternary TF-VIIa-Xa complex is optimally positioned to cleave PARs, indicating that signaling events precede downstream coagulation activation. More intriguingly, the coagulant activity of the TF-VIIa complex can be disabled while preserving TF-VIIa’s ability to activate PAR2. The key regulatory switch is an extracellular, allosteric disulfide bond in TF that is targeted by protein disulfide isomerase for inactivation in a reductive, nitric oxide–dependent pathway. In addition, the TF-VIIa complex associates with integrins and through the TF cytoplasmic domain regulates integrin function. Deletion of the TF cytoplasmic domain in mice uncovered processes that are regulated by the TF-VIIa signaling complex in vivo and provided evidence that PAR2 is the central signaling receptor for TF-VIIa in angiogenesis and innate immune responses. Upstream direct TF-VIIa and downstream thrombin signaling appear to play nonredundant roles, and genetic mouse models will be essential to further dissect the signaling pathways that are controlled by protease-receptor complexes of the coagulation system in vivo.