TY - JOUR
T1 - Membrane-associated androgen receptor (AR) potentiates its transcriptional activities by activating heat shock protein 27 (HSP27)
AU - Li, Jianzhuo
AU - Fu, Xueqi
AU - Cao, Subing
AU - Li, Jing
AU - Xing, Shu
AU - Li, Dongying
AU - Dong, Yan
AU - Cardin, Derrick
AU - Park, Hee Won
AU - Mauvais-Jarvis, Franck
AU - Zhang, Haitao
N1 - Funding Information:
This work was supported by American Cancer Society Grants RSG-14-016-01-CCE, DOD W81XWH-12-1-0275, and W81XWH-14-1-0480; Louisiana Can-cer Research Consortium Fund; and the Tulane University Carol Lavin Ber-nick Faculty Grants (to H. Z.). This work was also supported by National Institutes of Health Grants R01 DK074970 and DK107444 (to F. M.-J.) and Department of Veterans Affairs Merit Review Award BX003725. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2018/8/17
Y1 - 2018/8/17
N2 - The androgen receptor (AR) is a ligand-activated nuclear receptor that plays a critical role in normal prostate physiology, as well as in the development and progression of prostate cancer. In addition to the classical paradigm in which AR exerts its biological effects in the nucleus by orchestrating the expression of the androgen-regulated transcriptome, there is considerable evidence supporting a rapid, nongenomic activity mediated by membrane-associated AR. Although the genomic action of AR has been studied in depth, the molecular events governing AR transport to the plasma membrane and the downstream AR signaling cascades remain poorly understood. In this study, we report that AR membrane transport is microtubule-dependent. Disruption of the function of kinesin 5B (KIF5B), but not of kinesin C3 (KIFC3), interfered with AR membrane association and signaling. Co-immunoprecipitation and pulldown assays revealed that AR physically interacts with KIF5B and that androgen enhances this interaction. Furthermore, we show that heat shock protein 27 (HSP27) is activated by membrane-associated AR and that HSP27 plays an important role in mediating AR-mediated membrane-to-nuclear signal transduction. Together, these results indicate that AR membrane translocation is mediated by the microtubule cytoskeleton and the motor protein KIF5B. By activating HSP27, membrane-associated AR potentiates the transcriptional activity of nuclear AR. We conclude that disruption of AR membrane translocation may represent a potential strategy for targeting AR signaling therapeutically in prostate cancer.
AB - The androgen receptor (AR) is a ligand-activated nuclear receptor that plays a critical role in normal prostate physiology, as well as in the development and progression of prostate cancer. In addition to the classical paradigm in which AR exerts its biological effects in the nucleus by orchestrating the expression of the androgen-regulated transcriptome, there is considerable evidence supporting a rapid, nongenomic activity mediated by membrane-associated AR. Although the genomic action of AR has been studied in depth, the molecular events governing AR transport to the plasma membrane and the downstream AR signaling cascades remain poorly understood. In this study, we report that AR membrane transport is microtubule-dependent. Disruption of the function of kinesin 5B (KIF5B), but not of kinesin C3 (KIFC3), interfered with AR membrane association and signaling. Co-immunoprecipitation and pulldown assays revealed that AR physically interacts with KIF5B and that androgen enhances this interaction. Furthermore, we show that heat shock protein 27 (HSP27) is activated by membrane-associated AR and that HSP27 plays an important role in mediating AR-mediated membrane-to-nuclear signal transduction. Together, these results indicate that AR membrane translocation is mediated by the microtubule cytoskeleton and the motor protein KIF5B. By activating HSP27, membrane-associated AR potentiates the transcriptional activity of nuclear AR. We conclude that disruption of AR membrane translocation may represent a potential strategy for targeting AR signaling therapeutically in prostate cancer.
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U2 - 10.1074/jbc.RA118.003075
DO - 10.1074/jbc.RA118.003075
M3 - Article
C2 - 29934310
AN - SCOPUS:85051699580
SN - 0021-9258
VL - 293
SP - 12719
EP - 12729
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 33
ER -