Cell Reports (Feb 2016)
Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors
- 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
Affiliations
- Mark R. Woodford
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Andrew W. Truman
- Department of Biological Sciences, University of North Carolina, Charlotte, NC 28223, USA
- Diana M. Dunn
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Sandra M. Jensen
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Richard Cotran
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Renee Bullard
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Mourad Abouelleil
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Kristin Beebe
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Donald Wolfgeher
- Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA
- Sara Wierzbicki
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Dawn E. Post
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Tiffany Caza
- Department of Pathology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Shinji Tsutsumi
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Barry Panaretou
- Institute of Pharmaceutical Science, Kings College London, London SE1 9NH, UK
- Stephen J. Kron
- Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA
- Jane B. Trepel
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Steve Landas
- Department of Pathology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Chrisostomos Prodromou
- Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
- Oleg Shapiro
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- William G. Stetler-Stevenson
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Dimitra Bourboulia
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Len Neckers
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Gennady Bratslavsky
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- Mehdi Mollapour
- Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
- DOI
- https://doi.org/10.1016/j.celrep.2015.12.084
- Journal volume & issue
-
Vol. 14,
no. 4
pp. 872 – 884
Abstract
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.
Keywords
- heat shock protein-90
- phosphorylation
- kinase
- phosphatase
- molecular chaperones
- mitotic checkpoint
- Mps1
- Cdc14
- renal cell carcinoma
