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mediates shear stress-dependent
activation of JNK in endothelial cells
1 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294; and 2 Max Planck Research Unit Molecular Cell Biology, University of Jena, 07747 Jena, Germany
Shear stress differentially activates
extracellular signal-regulated kinase (ERK) and c-Jun
NH2-terminal kinase (JNK) by
mechanisms involving G
i2 and
G
/
proteins, respectively, in bovine aortic endothelial cells
(BAEC). The early events in this signaling mechanism by which G
proteins regulate ERK and JNK in response to shear stress have not been
defined. Here we show that BAEC endogenously express a G
protein-dependent form of phosphatidylinositol 3-kinase, PI3K
, and
its activity is stimulated by shear stress. PI3K
activity was
measured in vitro using BAEC that were transiently transfected with an
epitope-tagged PI3K
(vsv-PI3K
). Exposure of BAEC to shear stress
rapidly and transiently stimulated the activity of vsv-PI3K
(maximum
by 15 s, with a return to basal after 1-min exposure to 5 dyn/cm2 shear stress). Activity of
vsv-PI3K
was stimulated by shear stress intensities as low as 0.5 dyn/cm2. Treatment of BAEC with an
inhibitor of PI3K, wortmannin, inhibited shear-dependent activation of
JNK but had no effect on that of ERK. Furthermore, expression of a
kinase-inactive mutant
(PI3K
K799R) in BAEC inhibited
the shear-dependent activation of JNK but not ERK. Taken together,
these results suggest that PI3K
selectively regulates the
shear-sensitive JNK pathway. This differential and novel signaling
pathway may be responsible for coordinating various mechanosensitive
events in endothelial cells.
mechanotransduction; extracellular signal-regulated kinase; G proteins; atherosclerosis
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