Coordinated Regulation of Serum- and Glucocorticoid-inducible Kinase 3 by a C-terminal Hydrophobic Motif and Hsp90-Cdc37 Chaperone Complex*
| Autor: | Len Neckers, Yuanzhong Wang, Wanping Xu, Dujin Zhou, Shiuan Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Proteasome Endopeptidase Complex
Chaperonins Lactams Macrocyclic Ubiquitin-Protein Ligases Amino Acid Motifs Cell Cycle Proteins Mitogen-activated protein kinase kinase Protein Serine-Threonine Kinases Biochemistry Mass Spectrometry MAP2K7 3-Phosphoinositide-Dependent Protein Kinases Mice Structure-Activity Relationship Cell Line Tumor Enzyme Stability Protein Interaction Mapping Benzoquinones Animals Humans ASK1 HSP90 Heat-Shock Proteins Phosphorylation Molecular Biology biology MAP kinase kinase kinase Cyclin-dependent kinase 4 Cyclin-dependent kinase 2 Ubiquitination Estrogens Cell Biology Cell biology Protein Structure Tertiary Enzyme Activation Protein Synthesis and Degradation Drug Resistance Neoplasm Proteolysis biology.protein Cyclin-dependent kinase complex Cyclin-dependent kinase 9 Hydrophobic and Hydrophilic Interactions Chromatography Liquid Protein Binding |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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