Regulation of the p21Ras-MAP kinase pathway by Factor Vila

In recent years it has become clear that factor Vila (FVIIa) is not a passive mediator involved in the linear transduction of the coagulation cascade, but actively engages target cells to induce signal transduction and that this signal transduction fulfills critical functions in angiogenesis, arteriosclerosis and inflammatory processes. The details of coagulation factordependent signal transduction are among the least understood in biology and thus we set out to establish the molecular events responsible for MAP kinase activation induced by the interaction of FVIIa with its cellular binding partner tissue factor (TF). We observed that in both BHK and HaCaT cells FVIIa-induced MAP kinase activation correlates with p21Ras activation, and that this p21Ras activation is essential for FVIIa-induced MAP kinase activation. In BHK p21Ras activation was mediated by the activation of protein kinase C, whereas stimulation of the Src kinase family mediated FVIIa-dependent p21Ras activation in HaCaT cells. Thus p21Ras activation is instrumental in FVIIa signal transduction and the FVIIa-dependent activation of p21Ras involves either PKC or Src-dependent mechanisms, maybe as a consequence of the cell type-specific expression FVIIa:TF-targeted secondary receptors.