Cell Reports (Aug 2015)
c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells
- Diana M. Dunn,
- Mark R. Woodford,
- Andrew W. Truman,
- Sandra M. Jensen,
- Jacqualyn Schulman,
- Tiffany Caza,
- Taylor C. Remillard,
- David Loiselle,
- Donald Wolfgeher,
- Brian S.J. Blagg,
- Lucas Franco,
- Timothy A. Haystead,
- Soumya Daturpalli,
- Matthias P. Mayer,
- Jane B. Trepel,
- Rhodri M.L. Morgan,
- Chrisostomos Prodromou,
- Stephen J. Kron,
- Barry Panaretou,
- William G. Stetler-Stevenson,
- Steve K. Landas,
- Len Neckers,
- Gennady Bratslavsky,
- Dimitra Bourboulia,
- Mehdi Mollapour
Affiliations
- Diana M. Dunn
- Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
- Mark R. Woodford
- Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
- Andrew W. Truman
- Department of Biological Sciences, University of North Carolina Charlotte, Charlotte, NC 28223, USA
- Sandra M. Jensen
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Jacqualyn Schulman
- Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
- Tiffany Caza
- Department of Pathology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
- Taylor C. Remillard
- Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
- David Loiselle
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
- Donald Wolfgeher
- Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA
- Brian S.J. Blagg
- Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
- Lucas Franco
- Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
- Timothy A. Haystead
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
- Soumya Daturpalli
- Zentrum für Molekulare Biologie der Universitat Heidelberg, DKFZ-ZMBH-Alliance, Heidelberg 69120, Germany
- Matthias P. Mayer
- Zentrum für Molekulare Biologie der Universitat Heidelberg, DKFZ-ZMBH-Alliance, Heidelberg 69120, Germany
- Jane B. Trepel
- Developmental Therapeutics Branch, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Rhodri M.L. Morgan
- Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
- Chrisostomos Prodromou
- Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK
- Stephen J. Kron
- Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA
- Barry Panaretou
- Institute of Pharmaceutical Science, Kings College London, London SE1 9NH, UK
- William G. Stetler-Stevenson
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA
- Steve K. Landas
- Department of Pathology, SUNY Upstate Medical University, 750 East 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 East Adams Street, Syracuse, NY 13210, USA
- Dimitra Bourboulia
- Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
- Mehdi Mollapour
- Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
- DOI
- https://doi.org/10.1016/j.celrep.2015.07.004
- Journal volume & issue
-
Vol. 12,
no. 6
pp. 1006 – 1018
Abstract
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.
