Construction of the Androgen Receptor Interactome: A Molecular Framework for Probing Genetic Interactions in Androgen-Dependent Signaling

雄激素受体是一种强大的性类固醇激素受体，介导体内平衡和病理 人类荷尔蒙反应系统的功能。在过去的30年里，自从原始克隆人 雄激素受体基因，雄激素受体功能的分子洞察，包括正常和病理， 是从发现结合和调节雄激素受体活性的蛋白质中收集到的。这些 雄激素受体相互作用蛋白，更为人所知的是AR-相互作用体，构成了一个功能多样的 在细胞水平上调节雄激素受体在空间和时间上的功能的蛋白质谱。喜欢 其他性激素受体家族成员中，雄激素受体是一种粘性很强的受体。它有更多 超过350个结合伙伴，这使得雄激素受体可以作为中枢来调节细胞信号转导 通过与AR-互动组的动态蛋白质相互作用，在分子水平上。不幸的是，AR- 互动组随着时间的推移继续增长，目前还看不到明显的结束。我们无法定义AR-互动组 一个单一的细胞模型使其几乎不可能在实验上复制AR相互作用组和 了解他们的协调行动如何在空间和时间上调节AR依赖的信号。因此， AR依赖信号的定量和预测模型充其量仍是推测的。我们的科学研究 前提是，对细胞中AR-相互作用组的仔细注释和发现将为 了解这一亚蛋白质组如何参与雄激素受体的生理和病理功能 激素反应系统。因此，我们提出了一个实验方案来注释AR-互动组 在雄激素敏感的细胞模型中使用尖端的定量蛋白质组学技术。我们的蛋白质组 这些方法将定义细胞内AR-相互作用体的时空图，并为探索奠定基础 组成AR-相互作用体的蛋白质复合体内部和之间的遗传关系。蛋白质组学 这些发现将使我们能够开发细胞系统中AR依赖信号的可测试模型。这些型号 将提供一个分子框架来理解雄激素介导的信号如何在 动态平衡和病理状态。更重要的是，它们将指导发现新的可用药靶点 在AR相互作用体之间，从而破坏的AR依赖的信号可以在雄激素受体中被减弱- 折磨人类生殖系统和非生殖系统的相关病理。

Androgen receptor is a powerful sex-steroid hormone receptor that mediates homeostatic and pathological functions in hormone-responsive systems in humans. Over the past 30 years, since the original cloning of the androgen receptor cDNA, molecular insights into androgen receptor function, both normal and pathological, have been gleaned from the discovery of proteins that bind and regulate androgen receptor activity. These androgen receptor-interacting proteins, better known as the AR-interactome, constitute a functionally diverse spectrum of proteins that modulate androgen receptor function in space and time at the cellular level. Like other sex-steroid hormone receptor family members, androgen receptor is a very sticky receptor. It has more than 350 binding partners, which allows androgen receptor to serve as a hub to regulate cellular signaling at the molecular level through dynamic protein interactions with the AR-interactome. Unfortunately, the AR- interactome continues to grow over time with no clear end in sight. Our inability to define the AR-interactome in a single cellular model has made it nearly impossible to experimentally replicate the AR-interactome and understand how their coordinated actions regulate AR-dependent signaling in space and time. Thus, quantitative and predictive models of AR-dependent signaling remain speculative at best. Our scientific premise is that the careful annotation and discovery of the AR-interactome in cells will lay the foundation for understanding how this subproteome contributes to physiologic and pathologic androgen receptor functions in hormone-responsive systems. Thus, we have proposed an experimental plan to annotate the AR-interactome in androgen-sensitive cellular models using cutting-edge, quantitative proteomic techniques. Our proteomic approaches will define a spatiotemporal map of the AR-interactome in cells, and lay the foundation for probing genetic relationships within and between protein complexes comprising the AR-interactome. The proteomic findings will allow us to develop testable models of AR-dependent signaling in cellular systems. These models will provide a molecular framework to understand how androgen-mediated signaling operates under homeostatic and pathological states. More importantly, they will guide the discovery of novel druggable targets among the AR-interactome so that corrupted AR-dependent signaling can be attenuated in androgen receptor- related pathologies that afflict reproductive and non-reproductive systems in humans.