Abstract
SGK-1 (serum- and glucocorticoid-regulated kinase-1), a member of the AGC protein kinase family, plays an important role in regulating ion channel expression and contributes to malignant epithelial cell proliferation and survival. SGK-1 activity is regulated on three levels: transcriptional induction following a variety of environmental and intracellular stresses, proteasomal degradation, and phosphorylation. Here we report that phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of SGK-1 requires formation of a complex between SGK-1 and heat-shock protein 90 (Hsp90). Inactivation of Hsp90 by geldanamycin led to decreased SGK-1 phosphorylation independently of increased proteasomal protein degradation, and inhibition of PI3K activity by LY294002 appeared to eliminate SGK-1 phosphorylation at the same residues as those affected by geldanamycin treatment. Interestingly, geldanamycin-targeted phosphorylation sites were not limited to the known conserved PI3K-dependent sites Thr-256 and Ser-422 in SGK-1 but included additional unknown PI3K-dependent residues. Inhibition of Hsp90 also resulted in a complete loss of SGK-1 kinase activity, suggesting that Hsp90 activity is essential for regulating the PI3K/SGK-1 pathway.
Highlights
In addition to transcriptional induction following a physiological stressor, SGK-1 protein levels are tightly regulated via ubiquitin modification and rapid proteasome-mediated degradation [13]
We demonstrate that heat shock protein 90 (Hsp90) is required for phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of SGK-1, and that the phosphorylated residues appear to include both previously described Thr-256 and Ser-422 as well as additional unknown amino acid(s)
Phorylated species of SGK-1 following GA treatment (Fig. 4C, lanes 6 – 8). These results suggest that very high levels of the PI3K pathway activation by p110 CAAX can overcome a loss of Hsp90 function, perhaps by allowing SGK-1 to be phosphorylated despite suboptimal protein folding
Summary
In addition to transcriptional induction following a physiological stressor, SGK-1 protein levels are tightly regulated via ubiquitin modification and rapid proteasome-mediated degradation [13]. Hsp90-dependent phosphorylation plays a critical role in SGK-1 function because the rapid loss of phosphorylated SGK-1 species following GA treatment completely abrogates SGK-1 kinase activity.
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