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

Published

Journal 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.

Full Text

Duke Authors

Cited Authors

  • Dunn, DM; Woodford, MR; Truman, AW; Jensen, SM; Schulman, J; Caza, T; Remillard, TC; Loiselle, D; Wolfgeher, D; Blagg, BSJ; Franco, L; Haystead, TA; Daturpalli, S; Mayer, MP; Trepel, JB; Morgan, RML; Prodromou, C; Kron, SJ; Panaretou, B; Stetler-Stevenson, WG; Landas, SK; Neckers, L; Bratslavsky, G; Bourboulia, D; Mollapour, M

Published Date

  • August 11, 2015

Published In

Volume / Issue

  • 12 / 6

Start / End Page

  • 1006 - 1018

PubMed ID

  • 26235616

Pubmed Central ID

  • 26235616

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2015.07.004

Language

  • eng

Conference Location

  • United States