Membrane-associated androgen receptor (AR) potentiates its transcriptional activities by activating heat shock protein 27 (HSP27)
Membrane-associated androgen receptor (AR) potentiates its transcriptional activities by activating heat shock protein 27 (HSP27)
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DOI：
10.1074/jbc.ra118.003075
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发表时间：
2018-08-17
影响因子：
4.8
通讯作者：
Zhang, Haitao
中科院分区：
文献类型：
--
作者：
Li, Jianzhuo;Fu, Xueqi;Zhang, Haitao
雄激素受体（AR）是一种配体激活的核受体，在正常前列腺生理学以及前列腺癌的发展和进展中起关键作用。除了经典的范式，其中AR发挥其生物学效应的细胞核中的雄激素调节的转录组的表达，有相当多的证据支持快速，非基因组活性介导的膜相关的AR。虽然AR的基因组作用已被深入研究，但控制AR转运至质膜的分子事件和下游AR信号级联仍然知之甚少。在这项研究中，我们报告，AR膜转运是微管依赖性的。驱动蛋白5 B（KIF 5 B）功能的破坏，而不是驱动蛋白C3（KIFC 3），干扰AR膜的关联和信号。免疫共沉淀和pulldown试验表明，AR与KIF 5 B物理相互作用，雄激素增强这种相互作用。此外，我们发现热休克蛋白27（HSP 27）被膜相关AR激活，并且HSP 27在介导AR介导的膜-核信号转导中起重要作用。总之，这些结果表明，AR膜易位是由微管细胞骨架和马达蛋白KIF 5 B介导的。通过激活HSP 27，膜相关AR增强核AR的转录活性。我们的结论是，AR膜转位的中断可能代表一个潜在的策略，针对AR信号治疗前列腺癌。
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.