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Am J Physiol Heart Circ Physiol 275: H1898-H1904, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 5, H1898-H1904, November 1998

RAPID COMMUNICATION
Phosphatidylinositol 3-kinase gamma  mediates shear stress-dependent activation of JNK in endothelial cells

Young-Mi Go1, Heonyong Park1, Matthew C. Maland1, Victor M. Darley-Usmar1, Borislav Stoyanov2, Reinhard Wetzker2, and Hanjoong Jo1

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 Galpha i2 and Gbeta /gamma 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, PI3Kgamma , and its activity is stimulated by shear stress. PI3Kgamma activity was measured in vitro using BAEC that were transiently transfected with an epitope-tagged PI3Kgamma (vsv-PI3Kgamma ). Exposure of BAEC to shear stress rapidly and transiently stimulated the activity of vsv-PI3Kgamma (maximum by 15 s, with a return to basal after 1-min exposure to 5 dyn/cm2 shear stress). Activity of vsv-PI3Kgamma 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 (PI3Kgamma K799R) in BAEC inhibited the shear-dependent activation of JNK but not ERK. Taken together, these results suggest that PI3Kgamma 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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