title: Coordinated regulation of serum- and glucocorticoid-inducible kinase 3 by a C-terminal hydrophobic motif and Hsp90-Cdc37 chaperone complex.
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.
authors.affiliation: From the Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010 and.
authors.forename: Yuanzhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Wanping
authors.initials: W
authors.lastname: Xu
authors.forename: Dujin
authors.initials: D
authors.lastname: Zhou
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018833:Chaperonins / Q000378:metabolism*; D002853:Chromatography, Liquid; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D013058:Mass Spectrometry; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis / Q000187:drug effects; D013329:Structure-Activity Relationship; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D018833:Chaperonins; D004967:Estrogens; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C498362:CDC37 protein, human; C112969:HSP90AA1 protein, human; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C492951:Stub1 protein, mouse; C578562:PDPK1 protein, human; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases
keywords: CHIP; Cdc37; Hsp90; Hydrophobic Motif; Molecular Chaperone; PI 3-Kinase (PI3K); Protein Stability; SGK3; Ubiquitination