Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors.
Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors.
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DOI：
10.1016/j.celrep.2015.12.084
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发表时间：
2016-02-02
期刊：
影响因子：
8.8
通讯作者：
Mollapour M
中科院分区：
文献类型：
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作者：
Woodford MR;Truman AW;Dunn DM;Jensen SM;Cotran R;Bullard R;Abouelleil M;Beebe K;Wolfgeher D;Wierzbicki S;Post DE;Caza T;Tsutsumi S;Panaretou B;Kron SJ;Trepel JB;Landas S;Prodromou C;Shapiro O;Stetler-Stevenson WG;Bourboulia D;Neckers L;Bratslavsky G;Mollapour M
分子伴侣Hsp90保护对肿瘤生长和生存至关重要的非调控信号蛋白。肿瘤通常对Hsp90抑制剂表现出敏感性和选择性；然而，这种表型背后的分子机制仍然不清楚。我们报道了有丝分裂检查点激酶Mps1在Hsp90的氨基区磷酸化一个保守的苏氨酸残基。这反过来通过降低Hsp90 ATPase活性来调节伴侣功能，同时促进Hsp90与包括Mps1在内的激酶客户的联系。Hsp90的磷酸化对有丝分裂检查点也是必不可少的，因为它赋予Mps1稳定性和活性。我们确定CDC14是一种磷酸酶，可以使Hsp90去磷酸化，并破坏它与Mps1的相互作用。这会导致Mps1的降解，从而为其失活提供了一种机制。最后，Hsp90的磷酸化使细胞对其抑制物敏感，而升高的Mps1水平使肾癌对Hsp90药物具有选择性。Mps1的表达水平可以潜在地作为预测肿瘤对Hsp90抑制剂的反应的指标。
The molecular chaperone Hsp90 protects deregulated signaling proteins that are vital for tumor growth and survival. Tumors generally display sensitivity and selectivity toward Hsp90 inhibitors; however, the molecular mechanism underlying this phenotype remains undefined. We report that the mitotic checkpoint kinase Mps1 phosphorylates a conserved threonine residue in the amino-domain of Hsp90. This, in turn, regulates chaperone function by reducing Hsp90 ATPase activity while fostering Hsp90 association with kinase clients, including Mps1. Phosphorylation of Hsp90 is also essential for the mitotic checkpoint because it confers Mps1 stability and activity. We identified Cdc14 as the phosphatase that dephosphorylates Hsp90 and disrupts its interaction with Mps1. This causes Mps1 degradation, thus providing a mechanism for its inactivation. Finally, Hsp90 phosphorylation sensitizes cells to its inhibitors, and elevated Mps1 levels confer renal cell carcinoma selectivity to Hsp90 drugs. Mps1 expression level can potentially serve as a predictive indicator of tumor response to Hsp90 inhibitors.