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Swe1(Wee1)-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function
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posted on 2023-06-08, 08:29 authored by Mehdi Mollapour, Shinji Tsutsumi, Alison C Donnelly, Kristin Beebe, Mari J Tokita, Min-Jung Lee, Sunmin Lee, Giulia Morra, Dimitra Bourboulia, Bradley T Scroggins, Giorgio Colombo, Brian S Blagg, Barry Panaretou, William G Stetler-Stevenson, Jane B Trepel, Peter W Piper, Chrisostomos ProdromouChrisostomos Prodromou, Laurence PearlLaurence Pearl, Len NeckersSaccharomyces WEE1 (Swe1), the only "true" tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1(Wee1) phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90 alpha) in the N domain of Hsp90. Phosphorylation is cell-cycle associated and modulates the ability of Hsp90 to chaperone a selected clientele, including v-Src and several other kinases. Nonphosphorylatable mutants have normal ATPase activity, support yeast viability, and productively chaperone the Hsp90 client glucocorticoid receptor. Deletion of SWE1 in yeast - increases Hsp90 binding to its inhibitor geldanamycin, and pharmacologic inhibition/silencing of Wee1 sensitizes cancer cells to Hsp90 inhibitor-induced apoptosis. These findings demonstrate that Hsp90 chaperoning of distinct client proteins is differentially regulated by specific posttranslational modification of a unique subcellular pool of the chaperone, and they provide a strategy to increase the cellular potency of Hsp90 inhibitors.
History
Publication status
- Published
Journal
Molecular CellISSN
1097-2765Publisher
ElsevierExternal DOI
Issue
3Volume
37Page range
333-343Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
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