Activation of NF-κB by bradykinin through a Gα(q)- and Gβγ-dependent pathway that involves phosphoinositide 3-kinase and Akt

P. Xie, Darren D Browning, N. Hay, N. Mackman, R. D. Ye

Research output: Contribution to journalArticle

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Abstract

Recent work has suggested a role for the serine/threonine kinase Akt and IκB kinases (IKKs) in nuclear factor (NF)-κB activation. In this study, the involvement of these components in NF-κB activation through a G protein-coupled pathway was examined using transfected HeLa cells that express the B2-type bradykinin (BK) receptor. The function of IKK2, and to a lesser extent, IKK1, was suggested by BK-induced activation of their kinase activities and by the ability of their dominant negative mutants to inhibit BK-induced NF-κB activation. BK-induced NF-κB activation and IKK2 activity were markedly inhibited by RGS3T, a regulator of G protein signaling that inhibits Gα(q), and by two Gβγ scavengers. Co-expression of Gα(q) potentiated BK-induced NF-κB activation, whereas co-expression of either an activated Gα(q)(Q209L) or Gβ1γ2 induced IKK2 activity and NF-κB activation without BK stimulation. BK-induced NF-κB activation was partially blocked by LY294002 and by a dominant negative mutant of phosphoinositide 3-kinase (PI3K), suggesting that PI3K is a downstream effector of Gα(q) and Gβ1γ2 for NF-κB activation. Furthermore, BK could activate the PI3K downstream kinase Akt, whereas a catalytically inactive mutant of Akt inhibited BK-induced NF-κB activation. Taken together, these findings suggest that BK utilizes a signaling pathway that involves Gα(q), Gβ1γ2, PI3K, Akt, and IKK for NF-κB activation.

Original languageEnglish (US)
Pages (from-to)24907-24914
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number32
DOIs
StatePublished - Aug 11 2000
Externally publishedYes

Fingerprint

1-Phosphatidylinositol 4-Kinase
Bradykinin
Phosphatidylinositols
Phosphotransferases
Chemical activation
GTP-Binding Protein Regulators
Bradykinin B2 Receptors
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Protein-Serine-Threonine Kinases
HeLa Cells
GTP-Binding Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Activation of NF-κB by bradykinin through a Gα(q)- and Gβγ-dependent pathway that involves phosphoinositide 3-kinase and Akt. / Xie, P.; Browning, Darren D; Hay, N.; Mackman, N.; Ye, R. D.

In: Journal of Biological Chemistry, Vol. 275, No. 32, 11.08.2000, p. 24907-24914.

Research output: Contribution to journalArticle

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abstract = "Recent work has suggested a role for the serine/threonine kinase Akt and IκB kinases (IKKs) in nuclear factor (NF)-κB activation. In this study, the involvement of these components in NF-κB activation through a G protein-coupled pathway was examined using transfected HeLa cells that express the B2-type bradykinin (BK) receptor. The function of IKK2, and to a lesser extent, IKK1, was suggested by BK-induced activation of their kinase activities and by the ability of their dominant negative mutants to inhibit BK-induced NF-κB activation. BK-induced NF-κB activation and IKK2 activity were markedly inhibited by RGS3T, a regulator of G protein signaling that inhibits Gα(q), and by two Gβγ scavengers. Co-expression of Gα(q) potentiated BK-induced NF-κB activation, whereas co-expression of either an activated Gα(q)(Q209L) or Gβ1γ2 induced IKK2 activity and NF-κB activation without BK stimulation. BK-induced NF-κB activation was partially blocked by LY294002 and by a dominant negative mutant of phosphoinositide 3-kinase (PI3K), suggesting that PI3K is a downstream effector of Gα(q) and Gβ1γ2 for NF-κB activation. Furthermore, BK could activate the PI3K downstream kinase Akt, whereas a catalytically inactive mutant of Akt inhibited BK-induced NF-κB activation. Taken together, these findings suggest that BK utilizes a signaling pathway that involves Gα(q), Gβ1γ2, PI3K, Akt, and IKK for NF-κB activation.",
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