Phosphatidylinositol 3-kinase γ mediates shear stress-dependent activation of JNK in endothelial cells

Academic Article

Abstract

  • Shear stress differentially activates extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) by mechanisms involving Gα(i2) and Gβ/γ 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, PI3Kγ, and its activity is stimulated by shear stress. PI3Kγ activity was measured in vitro using BAEC that were transiently transfected with an epitope-tagged PI3Kγ (vsv-PI3Kγ). Exposure of BAEC to shear stress rapidly and transiently stimulated the activity of vsv-PI3Kγ (maximum by 15 s, with a return to basal after 1-min exposure to 5 dyn/cm2 shear stress). Activity of vsv-PI3Kγ 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 (PI3Kγ(K799R)) in BAEC inhibited the shear-dependent activation of JNK but not ERK. Taken together, these results suggest that PI3Kγ selectively regulates the shear-sensitive JNK pathway. This differential and novel signaling pathway may be responsible for coordinating various mechanosensitive events in endothelial cells.
  • Digital Object Identifier (doi)

    Author List

  • Go YM; Park H; Maland MC; Darley-Usmar VM; Stoyanov B; Wetzker R; Jo H
  • Volume

  • 275
  • Issue

  • 5 44-5