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Mps1 mediated phosphorylation of Hsp90 confers renal cell carcinoma sensitivity and selectivity to Hsp90 inhibitors
journal contribution
posted on 2023-06-21, 06:01 authored by Mark R Woodford, Andrew W Truman, Diana M Dunn, Sandra M Jensen, Richard Cotran, Renee Bullard, Mourad Abouelleil, Kristin Beebe, Donald Wolfgeher, Sara Wierzbicki, Dawn E Post, Tiffany Caza, Shinji Tsutsumi, Barry Panaretou, Stephen J Kron, Jane B Trepel, Steve Landas, Chrisostomos ProdromouChrisostomos Prodromou, Oleg Shapiro, William G Stetler-Stevenson, Dimitra Bourboulia, Len Neckers, Gennady Bratslavsky, Mehdi MollapourThe 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.
History
Publication status
- Published
File Version
- Published version
Journal
Cell ReportsISSN
2211-1247Publisher
ElsevierExternal DOI
Issue
4Volume
14Page range
872-884Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-06-07First Open Access (FOA) Date
2016-06-07First Compliant Deposit (FCD) Date
2016-06-07Usage metrics
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