Binding of the zymogen serine protease Factor VII (FVII) to its cellular cofactor tissue factor (TF) triggers blood coagulation. Several recent reports have suggested that the formation of this complex may serve additional functions. We have used cDNA arrays to study differential gene expression in response to the interaction of activated FVII (FVIIa) with TF on a human keratinocyte cell line. Of 931 mRNA species observed up to 6 h after FVIIa (10 nM) addition, 24 were significantly up-regulated in what may resemble a wound-type response. Responders included mRNA species coding for transcription regulators (c-fos, egr-1, ETR101, BTEB2, c-myc, fra-1, and tristetraproline), growth factors (amphiregulin, hbEGF, CTGF, and FGF-5), proinflammatory cytokines (IL-1, IL-8, LIF, and MIP2␣), proteins involved in cellular reorganization/migration (RhoE, uPAR, and collagenases 1 and 3), and others (PAI-2, cyclophilin, GADD45, Jagged1, and prostaglandin E 2 receptor). The transcriptional response to FVIIa was abrogated by antibodies to TF and left unaffected by hirudin. The pattern of genes induced suggests that the FVIIa⅐TF complex may play an active role in early wound repair as well as hemostasis. The former is a novel function ascribed to the complex that may also be contributing to the pathophysiology of unwarranted TF expression.
Tissue factor (TF)1 is a transmembrane glycoprotein that is constitutively expressed at high levels in tissues surrounding inner and outer bodily surfaces but not in cells that are in direct contact with blood (1). Disruption of these boundaries or induction of TF synthesis in monocytes (2) and endothelial cells (1) will allow plasma coagulation factors to establish contact with TF-expressing cells (1). TF then acts as a cofactor supporting activation of the zymogen serine protease FVII to FVIIa as well as the activity of FVIIa toward its substrates. Once formed, the FVIIa⅐TF complex triggers activation of zymogen coagulation proteases, which ultimately serve to cleave fibrinogen and generate a fibrin clot. Acting in concert with the accumulation of platelets, this is the main line of protection against blood loss after injury.Recent reports have shown that FVIIa can also induce TFdependent cellular signaling independent of downstream activation of the coagulation cascade (3-5). FVIIa binding to TF triggers intracellular calcium mobilization through phosphatidylinositol-specific phospholipase C (3, 4) as well as activation of mitogen-activated protein kinases (MAPKs) (5, 6) in several cell types.In this study we have addressed the physiological role of FVIIa⅐TF signaling by looking for transcriptional consequences of FVIIa-induced activation of HaCaT cells (7), a spontaneously transformed keratinocyte line much used as a keratinocyte model. These cells respond to regulatory signals in a similar manner to normal keratinocytes (8), express a range of epidermal differentiation markers (8), and are able to support epidermal differentiation and basement membrane formation in surface transplants (9)...