Factor VIIa/tissue factor-induced signaling via activation of Src-like kinases, phosphatidylinositol 3-kinase, and Rac

Tissue factor (TF), apart from activating the extrinsic pathway of the bloo d coagulation, is a principal regulator of embryonic angiogenesis and oncog enic neoangiogenesis, but also influences inflammation, leukocyte diapedesi s and tumor progression. The intracellular domain of TF lacks homology to o ther classes of receptors and hence the signaling mechanism is poorly under stood. Here we demonstrate that factor VIIa (the natural ligand for TF) ind uces the activation of the Src family members c-Src, Lyn, and Yes, and subs equently phosphatidylinositol 3-kinase (PI3K), followed by stimulation of c -Akt/protein kinase B as well as the small GTPases Rac and Cdc42. In turn R ac mediates p38 mitogen-activated protein (MAP) kinase activation and cytos keletal reorganization, whereas factor VIIa-induced p42/p44 MAP kinase stim ulation required PI3R enzymatic activity but was not inhibited by dominant negative Rac proteins. We propose that this Src family member/PI3K/Rac-depe ndent signaling pathway is a major mediator of factor VIIa/TF effects in pa thophysiology.