Phosphatidylinositol 3-kinase gamma 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 Galphai2 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 (PI3KgammaK799R) 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.
  • Published In

    Keywords

  • Animals, Cattle, Cells, Cultured, Endothelium, Vascular, Enzyme Activation, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mitogen-Activated Protein Kinase Kinases, Phosphatidylinositol 3-Kinases, Protein Kinases, Signal Transduction, Stress, Mechanical
  • Digital Object Identifier (doi)

    Author List

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

  • H1898
  • End Page

  • H1904
  • Volume

  • 275
  • Issue

  • 5