Differential functions of tissue factor in the trans-activation of cellular signalling pathways.
In this study we examined the ability of tissue factor (TF) alone, or in conjunction with factor VIIa, factor Xa and TFPI in activating a number of key signalling pathways associated with cellular growth, stress and differentiation responses in human endothelial cells. We used luciferase reporter systems to demonstrate the activation of p42/44 MAPK by the TF-FVIIa complex, mediated via the PAR1 receptor. TF alone was capable of interacting with the cell surface and was sufficient to activate the JNK-SAPK pathway and subsequently AP-1, but the level of activation was enhanced by the activity of FXa on PAR1 and 2. Furthermore, the phosphorylated form of the transmembrane-cytoplasmic domain of TF was directly responsible for activation of these pathways. CREB activation occurred in response to TF-FVIIa in a non-protease dependent manner but was lowered on addition of FXa. Finally, NFkappaB activation occurred in response to FVIIa or FXa, with the latter exhibiting higher levels of activation. In conclusion, we have shown that TF is capable of activating differing signalling pathways, via more than one mechanism. The differential influence of TF is modified depending on the presence of other coagulation factors and ultimately acts as a deciding factor in the determination of cellular fate.
Ettelaie
Camille
C
Biomedical Section, Department of Biological Sciences, University of Hull, Cottingham Road, Hull HU6 7RX, UK. C.Ettelaie@hull.ac.uk
Li
Chao
C
Collier
Mary E W
ME
Pradier
Amandine
A
Frentzou
G Alkistis
GA
Wood
Charlotte G
CG
Chetter
Ian C
IC
McCollum
Peter T
PT
Bruckdorfer
K Richard
KR
James
Nicola J
NJ
D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D015942:Factor VIIa / Q000378:metabolism / Q000494:pharmacology; D015951:Factor Xa / Q000378:metabolism / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D008074:Lipoproteins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015942:Factor VIIa; D015951:Factor Xa