Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function.
Swe1Wee1-dependent tyrosine phosphorylation of Hsp90 regulates distinct facets of chaperone function.
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DOI：
10.1016/j.molcel.2010.01.005
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发表时间：
2010-02-12
期刊：
影响因子：
16
通讯作者：
Neckers, Len
中科院分区：
文献类型：
--
作者：
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.;Neckers, Len
Swe 1（Saccharomyces WEE 1）是芽殖酵母中唯一的“真正”酪氨酸激酶，是Hsp 90客户蛋白。在这里，我们发现Swe 1 Wee 1磷酸化Hsp 90 N结构域中的保守酪氨酸残基（酵母Hsp 90中的Y24和人Hsp 90 α中的Y38）。磷酸化与细胞周期相关，并调节Hsp 90与选定客户（包括v-Src和其他几种激酶）的伴侣的能力。非磷酸化突变体具有正常的ATP酶活性，支持酵母活力，并有效地陪伴Hsp 90客户糖皮质激素受体。酵母中SWE 1的缺失增加了Hsp 90与其抑制剂格尔德霉素的结合，并且Wee 1的药理学抑制/沉默使癌细胞对Hsp 90抑制剂诱导的细胞凋亡敏感。这些研究结果表明，不同的客户端蛋白的Hsp 90伴侣是差异调节的特定的翻译后修饰的一个独特的亚细胞池的伴侣，他们提供了一种新的策略，以增加细胞的Hsp 90抑制剂的效力。
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.
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