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

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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.