title: c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells.
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.
authors.affiliation: 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.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Dunn
authors.affiliation: 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.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Woodford
authors.affiliation: 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.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Truman
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 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
authors.forename: Jacqualyn
authors.initials: J
authors.lastname: Schulman
authors.affiliation: Department of Pathology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Caza
authors.affiliation: 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.
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Remillard
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: David
authors.initials: D
authors.lastname: Loiselle
authors.affiliation: Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Wolfgeher
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Franco
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Haystead
authors.affiliation: Zentrum für Molekulare Biologie der Universitat Heidelberg, DKFZ-ZMBH-Alliance, Heidelberg 69120, Germany.
authors.forename: Soumya
authors.initials: S
authors.lastname: Daturpalli
authors.affiliation: Zentrum für Molekulare Biologie der Universitat Heidelberg, DKFZ-ZMBH-Alliance, Heidelberg 69120, Germany.
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Mayer
authors.affiliation: Developmental Therapeutics Branch, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
authors.forename: Rhodri M L
authors.initials: RM
authors.lastname: Morgan
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 Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kron
authors.affiliation: Institute of Pharmaceutical Science, Kings College London, London SE1 9NH, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Panaretou
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 Pathology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
authors.forename: Steve K
authors.initials: SK
authors.lastname: Landas
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 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East 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 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.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Bourboulia
authors.affiliation: 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.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mollapour
mesh_terms: D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008954:Models, Biological; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*
chemical_list: C515652:AHSA1 protein, human; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D016315:Proto-Oncogene Proteins c-abl; D046988:Proteasome Endopeptidase Complex