Swe1(Wee1)-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function

Mollapour, Mehdi, Tsutsumi, Shinji, Donnelly, Alison C, Beebe, Kristin, Tokita, Mari J, Lee, Min-Jung, Lee, Sunmin, Morra, Giulia, Bourboulia, Dimitra, Scroggins, Bradley T, Colombo, Giorgio, Blagg, Brian S, Panaretou, Barry, Stetler-Stevenson, William G, Trepel, Jane B, Piper, Peter W, Prodromou, Chrisostomos, Pearl, Laurence H and Neckers, Len (2010) Swe1(Wee1)-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function. Molecular Cell, 37 (3). pp. 333-343. ISSN 1097-2765

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Saccharomyces 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: EPrints Services
Date Deposited: 06 Feb 2012 21:00
Last Modified: 30 Nov 2012 17:09
URI: http://sro.sussex.ac.uk/id/eprint/29080
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