Seminars

Regulation of cell proliferation requires a balanced response to both growth and stress-related cues. This balance is often misregulated in human diseases, especially cancer. The ability of eukaryotic organisms to coordinate nutritional, hormonal, and stress-related signals occurs, in part, through the evolutionarily conserved TOR kinase-signaling network. TOR functions as part of two distinct protein complexes, TOR Complexes 1 and 2 (TORC1 and TORC2), where TORC1 is uniquely inhibited by the antibiotic and immunosuppressant rapamycin. Our efforts have focused on understanding the structure and function of TORC2, using budding yeast, S. cerevisiae, as a model system. Because TORC2 is not inhibited by rapamycin, our understanding of its role within cells is not as complete in comparison to TORC1. In this lecture, I will describe some of the tools we have developed to explore TORC2 in yeast and what we have learned about how the activity of this complex is regulated, including the role of upstream co-factors as well as the role of specific lipids and the importance of membrane interactions. I will also describe our ongoing studies to understand how TOR assembles with specific binding partners to form TORC1 versus TORC2 and how yeast provides a unique system for exploring structural principles that underlay complex formation. Finally, I will discuss our efforts to identify novel inhibitors of mammalian mTOR and our approach to use yeast to identify sites of drug interaction. Together these studies emphasize the ongoing utility of using yeast as a model organism to understand a fundamental pathway essential for health and homeostasis in humans.