Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors

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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Main Authors: 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, Mollapour, Mehdi
Format: Online
Language:English
Published: 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887101/
id pubmed-4887101
recordtype oai_dc
spelling pubmed-48871012016-05-31 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 Mollapour, Mehdi Article 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. 2016-01-21 2016-02-02 /pmc/articles/PMC4887101/ /pubmed/26804907 http://dx.doi.org/10.1016/j.celrep.2015.12.084 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author 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
Mollapour, Mehdi
spellingShingle 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
Mollapour, Mehdi
Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors
author_facet 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
Mollapour, Mehdi
author_sort Woodford, Mark R.
title 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_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_sort mps1 mediated phosphorylation of hsp90 confers renal cell carcinoma sensitivity and selectivity to hsp90 inhibitors
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.
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887101/
_version_ 1613586650643824640

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