Abstract
Serum- and glucocorticoid-inducible kinase 3 (SGK3) mediates a variety of cellular processes including membrane transport, cell proliferation, and survival, and it has been implicated in Akt-independent signaling downstream of oncogenic PIK3CA mutations (activating mutations in the α catalytic subunit of PI3K) in human cancers. However, the regulation of SGK3 is poorly understood. Here we report that SGK3 stability and kinase activation are regulated by the Hsp90-Cdc37 chaperone complex. Hsp90-Cdc37 associates with the kinase domain of SGK3 and acts in concert with a C-terminal hydrophobic motif of SGK3 to prevent Hsp70 association and ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein)-mediated degradation. Phosphorylation of hydrophobic motif triggers release of Cdc37 and concomitant association of 3-phosphoinositide dependent kinase 1 (PDK1) to activate SGK3. Our study provides new insights into regulation of SGK3 stability and activation and the rationale for application of Hsp90 inhibitors in treating SGK3-dependent cancers.
Keywords:
CHIP; Cdc37; Hsp90; Hydrophobic Motif; Molecular Chaperone; PI 3-Kinase (PI3K); Protein Stability; SGK3; Ubiquitination.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases / metabolism
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Amino Acid Motifs
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Animals
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Benzoquinones / pharmacology
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Chaperonins / metabolism*
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Chromatography, Liquid
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Drug Resistance, Neoplasm / drug effects
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Enzyme Activation / drug effects
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Enzyme Stability / drug effects
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Estrogens / pharmacology
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HSP90 Heat-Shock Proteins / metabolism*
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Humans
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Hydrophobic and Hydrophilic Interactions*
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Lactams, Macrocyclic / pharmacology
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Mass Spectrometry
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Mice
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Phosphorylation / drug effects
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding / drug effects
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Protein Interaction Mapping
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Protein Serine-Threonine Kinases / chemistry*
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Proteolysis / drug effects
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Structure-Activity Relationship
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination / drug effects
Substances
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Benzoquinones
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CDC37 protein, human
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Cell Cycle Proteins
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Estrogens
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HSP90 Heat-Shock Proteins
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HSP90AA1 protein, human
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Lactams, Macrocyclic
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17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
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Stub1 protein, mouse
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Ubiquitin-Protein Ligases
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3-Phosphoinositide-Dependent Protein Kinases
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PDPK1 protein, human
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Protein Serine-Threonine Kinases
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SGK3 protein, human
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Proteasome Endopeptidase Complex
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Chaperonins