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Cell Rep. 2015 Aug 11;12(6):1006-18. doi: 10.1016/j.celrep.2015.07.004. Epub 2015 Jul 30.

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

Author information

1
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
2
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
3
Department of Biological Sciences, University of North Carolina Charlotte, Charlotte, NC 28223, USA; Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
4
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
5
Department of Pathology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
6
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
7
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
8
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
9
Zentrum für Molekulare Biologie der Universitat Heidelberg, DKFZ-ZMBH-Alliance, Heidelberg 69120, Germany.
10
Developmental Therapeutics Branch, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
11
Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
12
Institute of Pharmaceutical Science, Kings College London, London SE1 9NH, UK.
13
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
14
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. Electronic address: mollapom@upstate.edu.

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.

PMID:
26235616
PMCID:
PMC4778718
DOI:
10.1016/j.celrep.2015.07.004
[Indexed for MEDLINE]
Free PMC Article

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