Activation of NF-kappa B by bradykinin through a G alpha(q)-and G beta gamma-dependent pathway that involves phosphoinositide 3-kinase and Akt

Recent work has suggested a role for the serine/threonine kinase Akt and I kappa B kinases (IKKs) in nuclear factor (NF)-kappa B activation. In this s tudy, the involvement of these components in NF-kappa B activation through a G protein-coupled pathway was examined using transfected HeLa cells that express the BE-type bradykinin (BK) receptor. The function of IKK2, and to a lesser extent, IKK1, was suggested by BK-induced activation of their kina se activities and by the ability of their dominant negative mutants to inhi bit BK-induced NF-kappa B activation. BK-induced NF-kappa B activation and IKK2 activity were markedly inhibited by RGS3T, a regulator of G protein si gnaling that inhibits G alpha(q), and by two G beta gamma scavengers. Go-ex pression of G alpha q potentiated BK-induced NF-kappa B activation, whereas co-expression of either an activated G alpha q(Q209L) or G beta(1)gamma(2) induced IKK2 activity and NF-kappa B activation without BK stimulation. BK -induced NF-kappa B activation was partially blocked by LY294002 and by a d ominant negative mutant of phosphoinositide 3-kinase (P13K), suggesting tha t P13K is a downstream effector of G alpha(q) and G beta(1)gamma(2) for NF- kappa B activation. Furthermore, BK could activate the PI8K downstream kina se Akt, whereas a catalytically inactive mutant of Akt inhibited BK-induced NF-kappa B activation. Taken together, these findings suggest that BK util izes a signaling pathway that involves G alpha(q), G beta(1)gamma(2), P13K1 Akt, and IKK for NF-kappa B activation.