title: The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling.
abstract: FKBP52 and β-catenin have emerged in recent years as attractive targets for prostate cancer treatment. β-catenin interacts directly with the androgen receptor (AR) and has been characterized as a co-activator of AR-mediated transcription. FKBP52 is a positive regulator of AR in cellular and whole animal models and is required for the development of androgen-dependent tissues. We previously characterized an AR inhibitor termed MJC13 that putatively targets the AR BF3 surface to specifically inhibit FKBP52-regulated AR signaling. Predictive modeling suggests that β-catenin interacts with the AR hormone binding domain on a surface that overlaps with BF3. Here we demonstrate that FKBP52 and β-catenin interact directly in vitro and act in concert to promote a synergistic up-regulation of both hormone-independent and -dependent AR signaling. Our data demonstrate that FKBP52 promotes β-catenin interaction with AR and is required for β-catenin co-activation of AR activity in prostate cancer cells. MJC13 effectively blocks β-catenin interaction with the AR LBD and the synergistic up-regulation of AR by FKBP52 and β-catenin. Our data suggest that co-regulation of AR by FKBP52 and β-catenin does not require FKBP52 PPIase catalytic activity, nor FKBP52 binding to Hsp90. However, the FKBP52 proline-rich loop that overhangs the PPIase pocket is critical for synergy.
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America; Department of Chemistry and Biochemistry, Kettering University, Flint, Michigan, United States of America.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Storer Samaniego
authors.affiliation: Genomic Medicine, The Methodist Hospital Research Institute, Houston, Texas, United States of America.
authors.forename: Ji Ho
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Genomic Medicine, The Methodist Hospital Research Institute, Houston, Texas, United States of America.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Chattopadhyay
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Olivares
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Naihsuan
authors.initials: N
authors.lastname: Guy
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Sivils
authors.affiliation: Department of Biology and Biochemistry and Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, United States of America.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Dey
authors.affiliation: Department of Biochemistry and Biophysics, The University of California, San Francisco, California, United States of America.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yumoto
authors.affiliation: Department of Biochemistry and Biophysics, The University of California, San Francisco, California, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fletterick
authors.affiliation: Department of Biology and Biochemistry and Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, United States of America.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Strom
authors.affiliation: Department of Biology and Biochemistry and Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, United States of America.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Genomic Medicine, The Methodist Hospital Research Institute, Houston, Texas, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, Texas, United States of America.
authors.forename: Marc B
authors.initials: MB
authors.lastname: Cox
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism*; D015290:Second Messenger Systems; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011944:Receptors, Androgen; D051176:beta Catenin; D022021:Tacrolimus Binding Proteins