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 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.
Versteeg
H H
HH
Laboratory for Experimental Internal Medicine, G2-130, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands,
Hoedemaeker
I
I
Diks
S H
SH
Stam
J C
JC
Spaargaren
M
M
van Bergen En Henegouwen
P M
PM
van Deventer
S J
SJ
Peppelenbosch
M P
MP
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D015942:Factor VIIa / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D013925:Thromboplastin / Q000494:pharmacology*; D000077191:Wortmannin; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology*
D000730:Androstadienes; D013925:Thromboplastin; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015942:Factor VIIa; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D000077191:Wortmannin