PXD001737

PXD001737 is an original dataset announced via ProteomeXchange.

Title	c-Abl Dependent Tyrosine Phosphorylation of theCo-chaperone Aha1 Regulates Interaction with Hsp90
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.
HostingRepository	PRIDE
AnnounceDate	2015-08-06
AnnouncementXML	Submission_2015-08-06_04:11:07.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Donald Wolfgeher
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue; phosphorylated residue; (18)O label at both C-terminal oxygens; formylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2015-01-27 01:52:15	ID requested
⏵ 1	2015-08-06 04:11:08	announced

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, 12(6):1006-18(2015) [pubmed]

curator keyword: Biomedical, Biological

submitter keyword: 18O Labeling, Q-Exactive, Quantative Proteomics, Molecular chaperone, Co-chaperone, Heat Shock Protein 90, Aha1, c-Abl

Mehdi Mollapour
contact affiliation	Department of Urology, Department of Biochemistry and Molecular Biology, Cancer Research Institute, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY 13210, USA
contact email	mollapom@upstate.edu
lab head
Donald Wolfgeher
contact affiliation	University of Chicago
contact email	donw@uchicago.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD001737
     1. Label: PRIDE project
     2. Name: c-Abl Dependent Tyrosine Phosphorylation of theCo-chaperone Aha1 Regulates Interaction with Hsp90