Tissue factor cytoplasmic domain stimulates migration by activation of the GTPase Rac1 and the mitogen-activated protein kinase p38

• Published in: Circulation (New York, N.Y.) Vol. 111; no. 3; pp. 349 - 355
• Main Authors: OTT, Ilka, WEIGAND, Berthold, MICHL, Ruth, SEITZ, Isabell, SABBARI-ERFANI, Nooshin, NEUMANN, Franz-Josef, SCHÖMIG, Albert
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 25.01.2005
• Subjects: Associated diseases and complications; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Line, Tumor; Cell Movement; Coronary heart disease; Cytoplasm - metabolism; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation; Factor VIIa - pharmacology; Factor VIIa - physiology; Heart; Humans; Medical sciences; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Structure, Tertiary; rac GTP-Binding Proteins - metabolism; Signal Transduction; Thromboplastin - physiology; Angiogenesis; Enzyme; Triphosphoric monoester hydrolases; Tissue factor; Mitogen-activated protein kinase; dGTPase; Hydrolases; Cardiovascular disease; Esterases; coagulation; Endothelium
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000153333.52294.42

Tissue factor (TF), the surface receptor for the serine protease factor VIIa (FVIIa) and the initiator of the extrinsic coagulation cascade, supports vessel development and tumor metastasis by activation of extracellular, protease-dependent signaling pathways. The molecular mechanisms that do not require proteolytic activity of FVIIa are not yet known. The aim of the study, therefore, was to investigate the effects of active-site-inhibited FVIIa (FFR-FVIIa) on TF-mediated signaling. After stimulation with FVIIa and FFR-FVIIa, migration and activation of the GTPase Rac (Rac1) or the mitogen-activated protein kinase p38 (p38) were analyzed in J82 cells. FVIIa and FFR-FVIIa stimulated migration and activation of Rac1 and p38 in a TF-specific, dose- and time-dependent manner. Enhancement of migration required activation of Rac1 and p38, because it was abolished after inhibition with SB203580 or overexpression of dominant negative p38 and Rac1. The cytoplasmic domain of TF was necessary because no effects of FFR-FVIIa could be detected after transfection of a TF deletion mutant lacking the cytoplasmic domain. We identified a novel signaling pathway through which TF stimulates migration by activation of p38 and Rac1 independent of the proteolytic activity of FVIIa but dependent on the cytoplasmic domain of TF. Binding of FFR-VIIa to TF may stimulate vessel wall remodeling by enhancement of migration through activation of Rac1 and p38. This novel link may provide an insight into the understanding of the nonhemostatic functions of TF.