title: Signal transduction via the mitogen-activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor.
abstract: The putative role of tissue factor (TF) as a receptor involved in signal transduction is indicated by its sequence homology to cytokine receptors (Bazan, J. F. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 6934-6938). Signal transduction induced by binding of FVIIa to cells expressing TF was studied with baby hamster kidney (BHK) cells stably transfected with TF and with a reporter gene construct encoding a luciferase gene under transcriptional control of tandem cassettes of signal transducer and activator of transcription (STAT) elements and one serum response element (SRE). FVIIa induced a significant luciferase response in cells expressing TF, BHK(+TF), but not in cells without TF. The BHK(+TF) cells responded to the addition of FVIIa in a dose-dependent manner, whereas no response was observed with active site-inhibited FVIIa, which also worked as an antagonist to FVIIa-induced signaling. Activation of the p44/42 MAPK pathway upon binding of FVIIa to TF was demonstrated by suppression of signaling with the specific kinase inhibitor PD98059 and demonstration of a transient p44/42 MAPK phosphorylation. No stimulation of p44/42 MAPK phosphorylation was observed with catalytically inactive FVIIa derivatives suggesting that the catalytic activity of FVIIa was obligatory for activation of the MAPK pathway. Signal transduction caused by a putative generation of FXa activity was excluded by experiments showing that FVIIa/TF-induced signaling was not quenched by tick anticoagulant protein, just as addition of FXa could not induce phosphorylation of p44/42 MAPK in BHK(+TF) cells. These results suggest a specific mechanism by which binding of FVIIa to cell surface TF independent of coagulation can modulate cellular functions and possibly play a role in angiogenesis and tumor metastasis as indicated by several recent observations.
authors.affiliation: Bioimage, Health Care Discovery, Novo Nordisk A/S, Hagedornsvej 1, DK-2820 Gentofte, Denmark.
authors.forename: L K
authors.initials: LK
authors.lastname: Poulsen
authors.forename: N
authors.initials: N
authors.lastname: Jacobsen
authors.forename: B B
authors.initials: BB
authors.lastname: Sørensen
authors.forename: N C
authors.initials: NC
authors.lastname: Bergenhem
authors.forename: J D
authors.initials: JD
authors.lastname: Kelly
authors.forename: D C
authors.initials: DC
authors.lastname: Foster
authors.forename: O
authors.initials: O
authors.lastname: Thastrup
authors.forename: M
authors.initials: M
authors.lastname: Ezban
authors.forename: L C
authors.initials: LC
authors.lastname: Petersen
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D004285:Dogs; D005167:Factor VII / Q000378:metabolism; D015942:Factor VIIa / Q000378:metabolism*; D005170:Factor X / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007668:Kidney / Q000166:cytology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D011994:Recombinant Proteins; D005167:Factor VII; D005170:Factor X; D013925:Thromboplastin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015942:Factor VIIa; D015951:Factor Xa; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one