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c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells

The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific “client” proteins. The intracellular signaling mechanisms directly regulating Aha1 association w...

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Autores principales: Dunn, Diana M., Woodford, Mark R., Truman, Andrew W., Jensen, Sandra M., Schulman, Jacqualyn, Caza, Tiffany, Remillard, Taylor C., Loiselle, David, Wolfgeher, Donald, Blagg, Brian S.J., Franco, Lucas, Haystead, Timothy A., Daturpalli, Soumya, Mayer, Matthias P., Trepel, Jane B., Morgan, Rhodri M.L., Prodromou, Chrisostomos, Kron, Stephen J., Panaretou, Barry, Stetler-Stevenson, William G., Landas, Steve K., Neckers, Len, Bratslavsky, Gennady, Bourboulia, Dimitra, Mollapour, Mehdi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778718/
https://www.ncbi.nlm.nih.gov/pubmed/26235616
http://dx.doi.org/10.1016/j.celrep.2015.07.004
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author Dunn, Diana M.
Woodford, Mark R.
Truman, Andrew W.
Jensen, Sandra M.
Schulman, Jacqualyn
Caza, Tiffany
Remillard, Taylor C.
Loiselle, David
Wolfgeher, Donald
Blagg, Brian S.J.
Franco, Lucas
Haystead, Timothy A.
Daturpalli, Soumya
Mayer, Matthias P.
Trepel, Jane B.
Morgan, Rhodri M.L.
Prodromou, Chrisostomos
Kron, Stephen J.
Panaretou, Barry
Stetler-Stevenson, William G.
Landas, Steve K.
Neckers, Len
Bratslavsky, Gennady
Bourboulia, Dimitra
Mollapour, Mehdi
author_facet Dunn, Diana M.
Woodford, Mark R.
Truman, Andrew W.
Jensen, Sandra M.
Schulman, Jacqualyn
Caza, Tiffany
Remillard, Taylor C.
Loiselle, David
Wolfgeher, Donald
Blagg, Brian S.J.
Franco, Lucas
Haystead, Timothy A.
Daturpalli, Soumya
Mayer, Matthias P.
Trepel, Jane B.
Morgan, Rhodri M.L.
Prodromou, Chrisostomos
Kron, Stephen J.
Panaretou, Barry
Stetler-Stevenson, William G.
Landas, Steve K.
Neckers, Len
Bratslavsky, Gennady
Bourboulia, Dimitra
Mollapour, Mehdi
author_sort Dunn, Diana M.
collection PubMed
description The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific “client” proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity, enhances Hsp90 interaction with kinase clients, and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a regulatory paradigm, we also find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally, pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90, thereby hypersensitizing cancer cells to Hsp90 inhibitors both in vitro and ex vivo.
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spelling pubmed-47787182016-03-04 c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells Dunn, Diana M. Woodford, Mark R. Truman, Andrew W. Jensen, Sandra M. Schulman, Jacqualyn Caza, Tiffany Remillard, Taylor C. Loiselle, David Wolfgeher, Donald Blagg, Brian S.J. Franco, Lucas Haystead, Timothy A. Daturpalli, Soumya Mayer, Matthias P. Trepel, Jane B. Morgan, Rhodri M.L. Prodromou, Chrisostomos Kron, Stephen J. Panaretou, Barry Stetler-Stevenson, William G. Landas, Steve K. Neckers, Len Bratslavsky, Gennady Bourboulia, Dimitra Mollapour, Mehdi Cell Rep Article The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific “client” proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity, enhances Hsp90 interaction with kinase clients, and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a regulatory paradigm, we also find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally, pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90, thereby hypersensitizing cancer cells to Hsp90 inhibitors both in vitro and ex vivo. 2015-07-30 2015-08-11 /pmc/articles/PMC4778718/ /pubmed/26235616 http://dx.doi.org/10.1016/j.celrep.2015.07.004 Text en http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by/4.0/)
spellingShingle Article
Dunn, Diana M.
Woodford, Mark R.
Truman, Andrew W.
Jensen, Sandra M.
Schulman, Jacqualyn
Caza, Tiffany
Remillard, Taylor C.
Loiselle, David
Wolfgeher, Donald
Blagg, Brian S.J.
Franco, Lucas
Haystead, Timothy A.
Daturpalli, Soumya
Mayer, Matthias P.
Trepel, Jane B.
Morgan, Rhodri M.L.
Prodromou, Chrisostomos
Kron, Stephen J.
Panaretou, Barry
Stetler-Stevenson, William G.
Landas, Steve K.
Neckers, Len
Bratslavsky, Gennady
Bourboulia, Dimitra
Mollapour, Mehdi
c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells
title c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells
title_full c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells
title_fullStr c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells
title_full_unstemmed c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells
title_short c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells
title_sort c-abl mediated tyrosine phosphorylation of aha1 activates its co-chaperone function in cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778718/
https://www.ncbi.nlm.nih.gov/pubmed/26235616
http://dx.doi.org/10.1016/j.celrep.2015.07.004
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