Mps1 mediated phosphorylation of Hsp90 confers renal cell carcinoma sensitivity and selectivity to Hsp90 inhibitors

Woodford, Mark R, Truman, Andrew W, Dunn, Diana M, Jensen, Sandra M, Cotran, Richard, Bullard, Renee, Abouelleil, Mourad, Beebe, Kristin, Wolfgeher, Donald, Wierzbicki, Sara, Post, Dawn E, Caza, Tiffany, Tsutsumi, Shinji, Panaretou, Barry, Kron, Stephen J, Trepel, Jane B, Landas, Steve, Prodromou, Chrisostomos, Shapiro, Oleg, Stetler-Stevenson, William G, Bourboulia, Dimitra, Neckers, Len, Bratslavsky, Gennady and Mollapour, Mehdi (2016) Mps1 mediated phosphorylation of Hsp90 confers renal cell carcinoma sensitivity and selectivity to Hsp90 inhibitors. Cell Reports, 14 (4). pp. 872-884. ISSN 2211-1247

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Abstract

The molecular chaperone Hsp90 protects deregu- lated signaling proteins that are vital for tumor growth and survival. Tumors generally display sensi- tivity 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 dis- rupts its interaction with Mps1. This causes Mps1 degradation, thus providing a mechanism for its inactivation. Finally, Hsp90 phosphorylation sensi- tizes 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.

Item Type: Article
Keywords: Heat shock protein-90, Phosphorylation, Kinase, Phosphatase, Molecular chaperones, Mitotic checkpoint, Mps1, Cdc14, Renal cell carcinoma
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science
Q Science > QP Physiology > QP0501 Animal biochemistry
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens
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Depositing User: Chrisostomos Prodromou
Date Deposited: 07 Jun 2016 10:05
Last Modified: 11 Sep 2017 07:53
URI: http://sro.sussex.ac.uk/id/eprint/61353

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