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

J Thromb Haemost. 2008 Sep;6(9):1550-7. doi: 10.1111/j.1538-7836.2008.03091.x. Epub 2008 Jul 19.


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 BHK TF, 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 BHK TF, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Blotting, Western
  • Cells, Cultured
  • Cricetinae
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Factor VIIa / metabolism*
  • Factor Xa / metabolism
  • GTP-Binding Proteins / metabolism
  • Humans
  • Phosphorylation
  • Receptor, PAR-2 / metabolism*
  • Signal Transduction
  • Thrombin / metabolism
  • Thromboplastin / metabolism*
  • Up-Regulation*


  • Cyclic AMP Response Element-Binding Protein
  • Receptor, PAR-2
  • Thromboplastin
  • Factor VIIa
  • Thrombin
  • Factor Xa
  • GTP-Binding Proteins