SGK 1 Phosphorylation of I B Kinase and p 300 Up - regulates NF - B Activity and Increases N - Methyl - D - aspartate Receptor

Serumand 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 B kinase (IKK ) as a novel substrate of SGK1byusing biochemical andbioinformatic approaches. SGK1 directly phosphorylates IKK at Thr-23 and indirectly activates IKK at Ser-180. Furthermore, SGK1 enhanced nuclear factor B (NFB) activity and up-regulated N-methyl-D-aspartate receptor NR2A and NR2B expression through activation of IKK 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 , IKK activity is still required for IKKcomplex activation and for SGK1 phosphorylation and activation of NFB. In addition, SGK1 increased the acetylation of NFB through phosphorylationof p300 at Ser-1834, and this also leads toNFBactivation and NR2A and NR2B expression. Moreover, an endogenous stimulus of SGK1, insulin, increased IKK andNFBphosphorylation as well as NFB acetylation and NFB activity, but SGK1 small interfering RNA transfection blocked these effects of insulin. In examination of the functional significance of the SGK1-IKK -NFB signaling pathway, we found that transfection of the IKK double mutant (IKK 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.