title: Novel interaction between the co-chaperone Cdc37 and Rho GTPase exchange factor Vav3 promotes androgen receptor activity and prostate cancer growth.
abstract: Elevated androgen receptor (AR) activity in castration-resistant prostate cancer may occur through increased levels of AR co-activator proteins. Vav3, a guanine nucleotide exchange factor, is up-regulated following progression to castration resistance in preclinical models and is overexpressed in a significant number of human prostate cancers. Vav3 is a novel co-activator of the AR. We sought to identify Vav3 binding partners in an effort to understand the molecular mechanisms underlying Vav3 enhancement of AR activity and to identify new therapeutic targets. The cell division cycle 37 homolog (Cdc37), a protein kinase-specific co-chaperone for Hsp90, was identified as a Vav3 interacting protein by yeast two-hybrid screening. Vav3-Cdc37 interaction was confirmed by GST pulldown and, for native proteins, by co-immunoprecipitation experiments in prostate cancer cells. Cdc37 potentiated Vav3 co-activation of AR transcriptional activity and Vav3 enhancement of AR N-terminal-C-terminal interaction, which is essential for optimal receptor transcriptional activity. Cdc37 increased prostate cancer cell proliferation selectively in Vav3-expressing cells. Cdc37 did not affect Vav3 nucleotide exchange activity, Vav3 protein levels, or subcellular localization. Disruption of Vav3-Cdc37 interaction inhibited Vav3 enhancement of AR transcriptional activity and AR N-C interaction. Diminished Vav3-Cdc37 interaction also caused decreased prostate cancer cell proliferation selectively in Vav3-expressing cells. Taken together, we identified a novel Vav3 interacting protein that enhances Vav3 co-activation of AR and prostate cancer cell proliferation. Vav3-Cdc37 interaction may provide a new therapeutic target in prostate cancer.
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
authors.forename: Fayi
authors.initials: F
authors.lastname: Wu
authors.forename: Stephanie O
authors.initials: SO
authors.lastname: Peacock
authors.forename: Shuyun
authors.initials: S
authors.lastname: Rao
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Lemmon
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Burnstein
mesh_terms: D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018833:Chaperonins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism / Q000502:physiology*; D020798:Two-Hybrid System Techniques
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D018832:Molecular Chaperones; D051567:Proto-Oncogene Proteins c-vav; C496621:VAV3 protein, human; D005982:Glutathione Transferase; D018833:Chaperonins