Hsp90 regulates the phosphorylation and activity of serum- and glucocorticoid-regulated kinase-1.
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.
Belova
Larissa
L
Department of Medicine, Committee on Cancer Biology, The University of Chicago, Chicago, Illinois 60637, USA.
Brickley
Deanna R
DR
Ky
Betty
B
Sharma
Sanjay K
SK
Conzen
Suzanne D
SD
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
D016227:Benzoquinones; D002867:Chromones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D017874:Immediate-Early Proteins; D047029:Lactams, Macrocyclic; D009025:Morpholines; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C001277:geldanamycin