Regulation Of I Kappa B Kinase By G Beta L Through Recruitment Of The Protein Phosphatases

G protein beta-like (G beta L) is a member of WD repeat-containing family which are involved in various intracellular signaling events. In our previous report, we demonstrated that G beta L regulates TNF alpha-stimulated NF-kappa B signaling by interacting with and inhibiting phosphorylation of I kappa B kinase. However, G beta L itself does not seem to regulate IKK directly, because it contains no functional domains except WD domains. Here, using immunoprecipitation and proteomic analyses, we identified protein phosphatase 4 as a new binding partner of G beta L. We also found that G beta L interacts with PP2A and PP6, other members of the same phosphatase family. By interacting with protein phosphatases, which do not directly bind to IKK beta, G beta L mediates the association of phosphatases with IKK beta. Overexpression of protein phosphatases inhibited TNF kappa-induced activation of NF-kappa B signaling, which is an effect similar to that of G beta L overexpression. Down-regulation of G beta L by small interfering RNA diminished the inhibitory effect of phosphatases, resulting in restoration of NF-kappa B signaling. Thus, we propose that G beta L functions as a negative regulator of NF-kappa B signaling by recruiting protein phosphatases to the IKK complex.