TF:FVIIa‐specific activation of CREB upregulates proapoptotic proteins via protease‐activated receptor‐2

Background: Tissue factor (TF) and factor (F) VIIa are the primary initiators of the coagulation cascade, but also promote non‐hemostatic events, such as angiogenesis and tumor growth, via activation of protease activated receptor‐2 (PAR2). Our previous findings indicated that the TF:FVIIa complex activates signal transducer and activator of transcription (STAT) signaling, leading to cell survival in TF‐transfected baby hamster kidney (BHK) cells. Methods: Using BHKTF, keratinocytes (HaCaT) and human umbilical vein endothelial cells (HUVEC), FVIIa‐induced phosphorylation and activation of the transcription factor cyclic AMP‐responsive binding protein (CREB) were tested and compared to that elicited by thrombin and FXa. In addition, the effect of these factors on cell survival and expression of apoptosis‐associated proteins was monitored. Results:: Factor VIIa led to a TF‐dependent, but TF cytoplasmic domain‐independent phosphorylation and activation of CREB in BHKTF, HaCaT and HUVEC. CREB activation was sensitive to blockade of the extracellular‐signal regulated kinase 1/2 pathway and PAR2. Surprisingly, FVIIa decreased cell survival in HaCaT cells but not other cell types and upregulated the pro‐apoptotic proteins Bak and Puma in a CREB‐dependent manner. Factor Xa, but not FIIa, induced phosphorylation of CREB, but did not have an effect on apoptosis. Conclusion: TF:FVIIa induces CREB phosphorylation and activation in several cell types, but TF:FVIIa induces pro‐apoptotic proteins and apoptosis only in selected cell types.