title: Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors.
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.
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Woodford
authors.affiliation: Department of Biological Sciences, University of North Carolina, Charlotte, NC 28223, USA.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Truman
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Dunn
authors.affiliation: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Jensen
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Cotran
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Bullard
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Mourad
authors.initials: M
authors.lastname: Abouelleil
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Beebe
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Wolfgeher
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Wierzbicki
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Post
authors.affiliation: Department of Pathology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Caza
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsutsumi
authors.affiliation: Institute of Pharmaceutical Science, Kings College London, London SE1 9NH, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Panaretou
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kron
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Department of Pathology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Landas
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Oleg
authors.initials: O
authors.lastname: Shapiro
authors.affiliation: Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Stetler-Stevenson
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Bourboulia
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
authors.forename: Gennady
authors.initials: G
authors.lastname: Bratslavsky
authors.affiliation: Department of Urology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA. Electronic address: mollapom@upstate.edu.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mollapour
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; D017346:Protein Serine-Threonine Kinases; C093416:MPS1 protein, S cerevisiae
keywords: Cdc14; Mps1; heat shock protein-90; kinase; mitotic checkpoint; molecular chaperones; phosphatase; phosphorylation; renal cell carcinoma