MassIVE MSV000080713

Imported Reanalysis Dataset Public PXD001737

c-Abl Dependent Tyrosine Phosphorylation of theCo-chaperone Aha1 Regulates Interaction with Hsp90

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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 also increases Hsp90 ATPase activity,enhancesHsp90 interaction with kinase clients,and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a new regulatory paradigm, we 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 bothin vitro and ex vivo. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: 18O Labeling ; Q-Exactive ; Quantative Proteomics ; Molecular chaperone ; Co-chaperone ; Heat Shock Protein 90 ; Aha1 ; c-Abl

Contact

Principal Investigators:
(in alphabetical order) 		Mehdi Mollapour, Department of Urology, Department of Biochemistry and Molecular Biology, Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY 13210, USA, N/A
Submitting User: ccms

Publications

Dunn DM, Woodford MR, Truman AW, Jensen SM, Schulman J, Caza T, Remillard TC, Loiselle D, Wolfgeher D, Blagg BS, Franco L, Haystead TA, Daturpalli S, Mayer MP, Trepel JB, Morgan RM, Prodromou C, Kron SJ, Panaretou B, Stetler-Stevenson WG, Landas SK, Neckers L, Bratslavsky G, Bourboulia D, Mollapour M.
c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells.
Cell Rep. 2015 Aug 11;12(6):1006-18. Epub 2015 Jul 30.

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