TY - JOUR
T1 - Factor VIIa/tissue factor-induced signaling via activation of Src-like kinases, phosphatidylinositol 3-kinase, and Rac
AU - Versteeg, H. H.
AU - Hoedemaeker, I.
AU - Diks, S. H.
AU - Stam, J. C.
AU - Spaargaren, M.
AU - van Bergen En Henegouwen, P. M.
AU - van Deventer, S. J.
AU - Peppelenbosch, M. P.
PY - 2000
Y1 - 2000
N2 - Tissue factor (TF), apart from activating the extrinsic pathway of the blood coagulation, is a principal regulator of embryonic angiogenesis and oncogenic neoangiogenesis, but also influences inflammation, leukocyte diapedesis and tumor progression. The intracellular domain of TF lacks homology to other classes of receptors and hence the signaling mechanism is poorly understood. Here we demonstrate that factor VIIa (the natural ligand for TF) induces the activation of the Src family members c-Src, Lyn, and Yes, and subsequently phosphatidylinositol 3-kinase (PI3K), followed by stimulation of c-Akt/protein kinase B as well as the small GTPases Rac and Cdc42. In turn Rac mediates p38 mitogen-activated protein (MAP) kinase activation and cytoskeletal reorganization, whereas factor VIIa-induced p42/p44 MAP kinase stimulation required PI3K enzymatic activity but was not inhibited by dominant negative Rac proteins. We propose that this Src family member/PI3K/Rac-dependent signaling pathway is a major mediator of factor VIIa/TF effects in pathophysiology
AB - Tissue factor (TF), apart from activating the extrinsic pathway of the blood coagulation, is a principal regulator of embryonic angiogenesis and oncogenic neoangiogenesis, but also influences inflammation, leukocyte diapedesis and tumor progression. The intracellular domain of TF lacks homology to other classes of receptors and hence the signaling mechanism is poorly understood. Here we demonstrate that factor VIIa (the natural ligand for TF) induces the activation of the Src family members c-Src, Lyn, and Yes, and subsequently phosphatidylinositol 3-kinase (PI3K), followed by stimulation of c-Akt/protein kinase B as well as the small GTPases Rac and Cdc42. In turn Rac mediates p38 mitogen-activated protein (MAP) kinase activation and cytoskeletal reorganization, whereas factor VIIa-induced p42/p44 MAP kinase stimulation required PI3K enzymatic activity but was not inhibited by dominant negative Rac proteins. We propose that this Src family member/PI3K/Rac-dependent signaling pathway is a major mediator of factor VIIa/TF effects in pathophysiology
U2 - https://doi.org/10.1074/jbc.M907635199
DO - https://doi.org/10.1074/jbc.M907635199
M3 - Article
C2 - 10844001
SN - 0021-9258
VL - 275
SP - 28750
EP - 28756
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -