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    Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function

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    Donnelly_2010.pdf (855.5Kb)
    Issue Date
    2010-02-12
    Author
    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. J.
    Panaretou, Barry
    Stetler-Stevenson, William G.
    Trepel, Jane B.
    Piper, Peter W.
    Prodromou, Chrisostomos
    Pearl, Laurence H.
    Neckers, Leonard
    Publisher
    Elsevier
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Metadata
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    Abstract
    Swe1 (Saccharomyces WEE1), the only “true” tyrosine kinase in budding yeast, is an Hsp90 client protein. Here we show that Swe1Wee1 phosphorylates a conserved tyrosine residue (Y24 in yeast Hsp90 and Y38 in human Hsp90α) 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. Non-phosphorylatable 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 post-translational modification of a unique subcellular pool of the chaperone, and they provide a novel strategy to increase the cellular potency of Hsp90 inhibitors.
    URI
    http://hdl.handle.net/1808/24587
    DOI
    https://doi.org/10.1016/j.molcel.2010.01.005
    Collections
    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Mollapour, M., Tsutsumi, S., Donnelly, A. C., Beebe, K., Tokita, M. J., Lee, M.-J., … Neckers, L. (2010). Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function. Molecular Cell, 37(3), 333–343. http://doi.org/10.1016/j.molcel.2010.01.005

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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