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J. Biol. Chem., Vol. 283, Issue 27, 18821-18831, July 4, 2008

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Hsp90 Regulates the Phosphorylation and Activity of Serum- and Glucocorticoid-regulated Kinase-1^*

Larissa Belova, Deanna R. Brickley¹, Betty Ky¹, Sanjay K. Sharma, and Suzanne D. Conzen^¶2

From the Department of Medicine, Committee on Cancer Biology, and the ^¶Ben May Department for Cancer Biology, The University of Chicago, Chicago, Illinois 60637

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.

Received for publication, April 30, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01CA089208. This work was also supported by University of Chicago Cancer Research Center Grant P30CA014599-32 (core facility support), the Riding for a Cure Foundation, and the University of Chicago Cancer Research Center Women's Auxiliary Board. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: The University of Chicago, 5841 South Maryland Ave., MC 2115, Chicago, IL 60637. Tel.: 773-834-2604; Fax: 773-834-0188; E-mail: sdconzen{at}uchicago.edu.

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