Requirement of phosphatidylinositol 3-kinase activity for bradykinin stimulation of NF-kappaB activation in cultured human epithelial cells.

Abstract

The signaling mechanisms utilized by bradykinin (BK) to activate the transcription factor nuclear factor kappaB (NF-kappaB) are poorly defined. We previously demonstrated that BK-stimulated NF-kappaB activation requires the small GTPase RhoA. We present evidence that BK-induced NF-kappaB activation both activates and requires phosphatidylinositol 3-kinase (PI 3-kinase) in A549 human epithelial cells. Pre-treatment with the PI 3-kinase-specific inhibitors, wortmannin, and LY294002 effectively blocked BK-induced PI 3-kinase activity. Wortmannin and LY294002 also abolished BK-induced NF-kappaB activation, as did transient transfection with a dominant negative mutant of the p85 subunit. BK-stimulated PI 3-kinase activity and NF-kappaB activation were sensitive to pertussis but not cholera toxin, suggesting that the B2 BK receptors transducing the response were coupled to Galphai or Galphao heterotrimeric G proteins. Tumor necrosis factor alpha (TNFalpha) also stimulated increased PI 3-kinase activity, however TNFalpha-stimulated NF-kappaB activation was not affected by the PI 3-kinase inhibitors or the p85 dominant negative mutant. These findings provide evidence that BK-induced NF-kappaB activation utilizes a signaling pathway that requires activity of both RhoA and PI 3-kinase and is distinct from the signaling pathway utilized by TNFalpha. Furthermore, we show that the p85 regulatory subunit is required for activation of PI 3-kinase activity by this G protein-coupled receptor.

• Authors: Z K Pan, S C Christiansen, A Ptasznik, B L Zuraw
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 274 Issue 15 Pg. 9918-22 (Apr 09 1999) ISSN: 0021-9258 [Print] United States
• PMID: 10187765 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Androstadienes
• Chromones
• Enzyme Inhibitors
• Morpholines
• NF-kappa B
• Phosphoinositide-3 Kinase Inhibitors
• Tumor Necrosis Factor-alpha
• Virulence Factors, Bordetella
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Bradykinin
• Wortmannin

Topics

• Adenocarcinoma (enzymology)
• Androstadienes (pharmacology)
• Bradykinin (pharmacology)
• Cells, Cultured
• Chromones (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Epithelial Cells (drug effects, metabolism)
• Humans
• Lung Neoplasms (enzymology)
• Morpholines (pharmacology)
• NF-kappa B (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (pharmacology)
• Virulence Factors, Bordetella (pharmacology)
• Wortmannin