Cryptic messages: Is noncoagulant tissue factor reserved for cell signaling?

Tissue factor (TF) is the principal initiator of blood clotting in response to vascular injury and in thrombotic disease (1). TF, an integral membrane protein, is normally excluded from the vascular compartment. Coagulation is initiated when TF is exposed to zymogen coagulation proteases in plasma upon vascular damage. TF first binds factor VII, supporting both its activation to VIIa and activation of factor X (Fig. 1). Factor Xa acts with its cellular cofactor Va to generate thrombin (IIa), which drives both fibrin deposition and platelet aggregation. Thrombin elicits signaling in cells through protease-activated receptors (PARs), a family of G protein-coupled receptors, which are activated proteolytically by unmasking of an N-terminal tethered ligand (Fig. 1) (2). In addition to hemostasis, TF expression and coagulant protease activation have been implicated in inflammation, vascular development, and cancer progression. Signaling by coagulant proteases is an important consequence of TF exposure in these settings. Factors VIIa and Xa have been shown to cleave and activate PAR2, the only PAR not activated by thrombin, and may act in concert with thrombin to elicit cellular responses to coagulation activation (Fig. 1). VIIa requires its cofactor TF to facilitate PAR2 cleavage and activation. The molecular determinants that specify TF function as a cofactor for cellular signaling versus coagulation are not known. In a recent issue of PNAS, Ahamed et al. (3) provide fascinating insight suggesting that coagulant and signaling TF may, in fact, be two different structural entities, that signaling TF may be the long-elusive encrypted TF, and that disulfide isomerization facilitates a dynamic and reversible switch between these two distinct functional TF species.