Serum- and glucocorticoid-inducible kinase (SGK) is a target of the MAPK/ERK signaling pathway that mediates memory formation in rats.

We have previously demonstrated that serum- and glucocorticoid-inducible kinase (SGK) plays a causal role in facilitating memory formation of spatial learning in rats, but the SGK signaling pathway involved in spatial memory formation is not known. The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) also plays an important role in memory formation. We therefore examined whether SGK is a downstream target of the MAPK/ERK signaling cascade and whether ERK signaling to SGK mediates spatial memory formation in rats. Results from an in vitro kinase assay revealed that ERK directly phosphorylates SGK at Ser78, but not at Thr256 and Ser422, whereas inhibition of ERK by PD98059 significantly decreased SGK phosphorylation at Ser78, Thr256 and Ser422 following spatial training. Prior administration of PD98059 also antagonized the enhancing effect of 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C activator that also causes ERK activation, on SGK phosphorylation and cAMP response element binding protein (CREB) phosphorylation. Moreover, TPA-induced SGK phosphorylation and CREB phosphorylation was abolished by prior SGKS78A mutant DNA transfection. By contrast, SGKS78A mutant DNA transfection to hippocampal area CA1 did not affect spatial memory formation, whereas SGKT256A mutant DNA transfection to area CA1 significantly impaired spatial memory formation. ERK was known to regulate sgk mRNA expression, but in the present study we have demonstrated that SGK is also a downstream target of the ERK signaling cascade; ERK directly phosphorylates SGK at Ser78 and indirectly activates SGK at Thr256 and Ser422 through unknown intermediate molecules. Furthermore, ERK activation of SGK is involved in spatial memory formation in rats.