학술논문
c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells
Document Type
article
Author
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
Source
Cell Reports, Vol 12, Iss 6, Pp 1006-1018 (2015)
Subject
Language
English
ISSN
2211-1247
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.