SIGNAL-TRANSDUCTION VIA THE MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY INDUCED BY BINDING OF COAGULATION-FACTOR VIIA TO TISSUE FACTOR

The putative role of tissue factor (TF) as a receptor involved in sign al transduction is indicated by its sequence homology to cytokine rece ptors (Bazan, J. F. (1990) Proc. Natl. Acad. Sci. U.S.A. 87 6934-6938) . Signal transduction induced by binding of FVIIa to cells expressing TF was studied with baby hamster kidney (BHK) cells stably transfected with TF and with a reporter gene construct encoding a luciferase gene under transcriptional control of tandem cassettes of signal transduce r and activator of transcription (STAT) elements and one serum respons e element (SRE). FVIIa induced a significant luciferase response in ce lls expressing TF, BHK(+TF), but not in cells without TF. The BHK(+TF) cells responded to the addition of FVIIa in a dose-dependent manner, whereas no response was observed with active site-inhibited FVIIa, whi ch also worked as an antagonist to FVIIa-induced signaling. Activation of the p44/42 MAPK pathway upon binding of FVIIa to TF was demonstrat ed by suppression of signaling with the specific kinase inhibitor PD98 059 and demonstration of a transient p44/42 MAPK phosphorylation. No s timulation of p44/42 MAPK phosphorylation was observed with catalytica lly inactive FVIIa derivatives suggesting that the catalytic activity of FVIIa was obligatory for activation of the MAPK pathway. Signal tra nsduction caused by a putative generation of FXa activity was excluded by experiments showing that FVIIa/TF-induced signaling was not quench ed by tick anticoagulant protein, just as addition of FXa could not in duce phosphorylation of p44/42 MAPK in BHK(+TF) cells. These results s uggest a specific mechanism by which binding of FVIIa to cell surface TF independent of coagulation can modulate cellular functions and poss ibly play a role in angiogenesis and tumor metastasis as indicated by several recent observations.