SGK1 Phosphorylation of IκB Kinase α and p300 Up-regulates NF-κB Activity and Increases N-Methyl-D-aspartate Receptor NR2A and NR2B Expression

Serum- and glucocorticoid-inducible kinase 1 (SGK1) is a downstream target of phosphatidylinositol 3-kinase signaling, and it regulates various cellular and physiological functions, but the SGK1 substrate proteins and genes regulated by SGK1 are less known. Here we have identified I kappa B kinase alpha (IKK alpha) as a novel substrate of SGK1 by using biochemical and bioinformatic approaches. SGK1 directly phosphorylates IKK alpha at Thr-23 and indirectly activates IKK alpha at Ser-180. Furthermore, SGK1 enhanced nuclear factor kappa B (NF-kappa B) activity and up-regulated N-methyl-D-aspartate receptor NR2A and NR2B expression through activation of IKK alpha at Thr-23 and Ser-180, and these two residues play an equally important role in mediating these effects of SGK1. Although SGK1 does not phosphorylate IKK beta, IKK beta activity is still required for IKK complex activation and for SGK1 phosphorylation and activation of NF-kappa B. In addition, SGK1 increased the acetylation of NF-kappa B through phosphorylation of p300 at Ser-1834, and this also leads to NF-kappa B activation and NR2A and NR2B expression. Moreover, an endogenous stimulus of SGK1, insulin, increased IKK alpha and NF-kappa B phosphorylation as well as NF-kappa B acetylation and NF-kappa B activity, but SGK1 small interfering RNA transfection blocked these effects of insulin. In examination of the functional significance of the SGK1-IKK alpha-NF-kappa B signaling pathway, we found that transfection of the IKK alpha double mutant (IKK alpha T23A/S180A) to rat hippocampus antagonized SGK-1-mediated spatial memory facilitation. Our results together demonstrated novel substrate proteins of SGK1 and novel SGK1 signaling pathways. Activation of these signaling pathways enhances NR2A and NR2B expression that is implicated in neuronal plasticity.