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Vol. 9, Issue 8, 1969-1980, August 1998
and
*Department of Pharmacology, School of Medicine and
Vascular endothelial cells are important in a variety of
physiological and pathophysiological processes. The growth and
functions of vascular endothelial cells are regulated both by soluble
mitogenic and differentiation factors and by interactions with the
extracellular matrix; however, relatively little is known about the
role of the matrix. In the present study, we investigate whether
integrin-mediated anchorage to a substratum coated with the
extracellular matrix protein fibronectin regulates growth factor
signaling events in human endothelial cells. We show that cell adhesion
to fibronectin and growth factor stimulation trigger distinct initial
tyrosine phosphorylation events in endothelial cells. Thus,
integrin-dependent adhesion of endothelial cells leads to
tyrosine phosphorylation of both focal adhesion kinase and
paxillin, but not of several growth factor receptors. Conversely, EGF
stimulation causes receptor autophosphorylation, with no effect on
focal adhesion kinase or paxillin tyrosine phosphorylation. Adhesion to
fibronectin, in the absence of growth factors, leads to activation of
MAPK. In addition, adhesion to fibronectin also potentiates growth
factor signaling to MAPK. Thus, polypeptide growth factor activation of
MAPK in anchored cells is far more effective than in cells maintained
in suspension. Other agonists known to activate MAPK were also examined
for their ability to activate MAPK in an anchorage-dependent manner.
The neuropeptide bombesin, the bioactive lipid lysophosphatidic acid
(LPA), and the cytokine tumor necrosis factor Department of Pediatrics, University of North Carolina,
Chapel Hill, North Carolina 27599
, which signal through diverse mechanisms, were all able to activate MAPK to a much
greater degree in fibronectin-adherent cells than in suspended cells.
In addition, tumor necrosis factor activation of c-Jun kinase (JNK)
was also much more robust in anchored cells. Together, these data
suggest a cooperation between integrins and soluble mitogens in
efficient propagation of signals to downstream kinases. This
cooperation may contribute to anchorage dependence of mitogenic cell
cycle progression.
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