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signaling events leading to tissue factor up-regulation via EGR-1 in endothelial cells
* Department of Vascular Biology and Thrombosis Research, VIRCC, University of Vienna, A-1235 Vienna, Austria; and
Department of Molecular Cell Biology, Max-Planck-Institute of Physiological and Clinical Research, D-61231 Bad Nauheim, Germany
1Correspondence: Department of Vascular Biology and Thrombosis Research, VIRCC, University of Vienna, Brunnerstrasse 59, A-1235 Vienna, Austria. E-mail: erhard.hofer{at}univie.ac.at
Tissue factor (TF) has been shown to be up-regulated in endothelial
cells by the inflammatory cytokine tumor necrosis factor 
(TNF-)
as well as by the main angiogenic factor VEGF. Since both stimuli
induce the transcription factor EGR-1, which is critically involved in
TF gene regulation, we used EGR-1-dependent TF induction as a model to
identify potential cross-talks between the various signal transduction
cascades initiated by VEGF and TNF-. The data show that at the MAP
kinase level, VEGF mainly activates ERK1/2 and p38 MAP kinases in human
endothelial cells. TNF- is able to activate all three MAP kinase
cascades as well as the classical inflammatory I
B/NFB pathway.
Furthermore, the MEK/ERK module of MAP kinases appears to act as the
convergence point of VEGF- and TNF--initiated signaling cascades,
which lead to the activation of EGR-1 and subsequent TF expression,
whereas the upstream signals are distinct. We found that induction of
TF by VEGF via EGR-1 is strongly PKC dependent. The TNF--initiated
MEK/ERK cascade connected to EGR-1 and TF expression is clearly less
sensitive to PKC inhibition. TNF--mediated activation of MEK/ERK and
EGR-1 can be blocked by adenoviral expression of a dominant negative
mutant of IKK2, whereas the VEGF signaling pathway is unaffected. Thus,
our data demonstrate a new link between the classical inflammatory
IKK/IB and the MEK/ERK cascades triggered by TNF-. The additional
finding that EGF induces ERK and EGR-1 in a PKC-independent manner and
that this signal is not sufficient to up-regulate TF emphasizes the
importance of a VEGF-specific signaling pattern for the induction of
TF.—Mechtcheriakova, D., Schabbauer, G., Lucerna, M., Clauss,
M., de Martin, R., Binder, B. R., Hofer, E. Specificity,
diversity, and convergence in VEGF and TNF- signaling events leading
to tissue factor up-regulation via EGR-1 in endothelial cells.
Key Words: endothelium • tissue factor • MAP kinases • inflammatory cytokines • angiogenic growth factors
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