Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors
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 c...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715015405 |
| _version_ | 1818180472224612352 |
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| author | 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 Prodromou Oleg Shapiro William G. Stetler-Stevenson Dimitra Bourboulia Len Neckers Gennady Bratslavsky Mehdi Mollapour |
| author_facet | 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 Prodromou Oleg Shapiro William G. Stetler-Stevenson Dimitra Bourboulia Len Neckers Gennady Bratslavsky Mehdi Mollapour |
| author_sort | Mark R. Woodford |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T21:20:18Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T21:20:18Z |
| publishDate | 2016-02-01 |
| publisher | Elsevier |
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| series | Cell Reports |
| spelling | doaj.art-94836c555dfb4543879e4bab5562ec972022-12-22T00:50:29ZengElsevierCell Reports2211-12472016-02-0114487288410.1016/j.celrep.2015.12.084Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 InhibitorsMark R. Woodford0Andrew W. Truman1Diana M. Dunn2Sandra M. Jensen3Richard Cotran4Renee Bullard5Mourad Abouelleil6Kristin Beebe7Donald Wolfgeher8Sara Wierzbicki9Dawn E. Post10Tiffany Caza11Shinji Tsutsumi12Barry Panaretou13Stephen J. Kron14Jane B. Trepel15Steve Landas16Chrisostomos Prodromou17Oleg Shapiro18William G. Stetler-Stevenson19Dimitra Bourboulia20Len Neckers21Gennady Bratslavsky22Mehdi Mollapour23Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USADepartment of Biological Sciences, University of North Carolina, Charlotte, NC 28223, USADepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USARadiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USADepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USADepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USADepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USAUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USADepartment of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USADepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USADepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USADepartment of Pathology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USAUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USAInstitute of Pharmaceutical Science, Kings College London, London SE1 9NH, UKDepartment of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USADevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USADepartment of Pathology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USAGenome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UKDepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USARadiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USADepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USAUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USADepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USADepartment of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USAThe 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.http://www.sciencedirect.com/science/article/pii/S2211124715015405heat shock protein-90phosphorylationkinasephosphatasemolecular chaperonesmitotic checkpointMps1Cdc14renal cell carcinoma |
| spellingShingle | 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 Prodromou Oleg Shapiro William G. Stetler-Stevenson Dimitra Bourboulia Len Neckers Gennady Bratslavsky Mehdi Mollapour Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors Cell Reports heat shock protein-90 phosphorylation kinase phosphatase molecular chaperones mitotic checkpoint Mps1 Cdc14 renal cell carcinoma |
| title | Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors |
| title_full | Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors |
| title_fullStr | Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors |
| title_full_unstemmed | Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors |
| title_short | Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors |
| title_sort | mps1 mediated phosphorylation of hsp90 confers renal cell carcinoma sensitivity and selectivity to hsp90 inhibitors |
| topic | heat shock protein-90 phosphorylation kinase phosphatase molecular chaperones mitotic checkpoint Mps1 Cdc14 renal cell carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715015405 |
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