Overview
Research Summary:
My lab studies the TORC1 signaling cascade, which senses nutrients and regulates gene expression, translation, and ribosome biogenesis and has been conserved over a billion years of evolution from yeast to humans. The Tor kinase is the target of the anti-proliferative and anti-aging drug rapamycin. The Tor kinases form two evolutionarily conserved multi-protein complexes known as TORC1 and TORC2. We have analyzed in detail the mechanisms of rapamycin action in the yeast Saccharomyces cerevisiae.
Over the past years, we conducted a structure-function analysis of the yeast and mammalian Tor kinases that revealed a novel toxic domain, which interacts with effectors or regulators of this signaling cascade. This analysis also showed that the Tor kinase domain is functionally conserved between yeast and humans. Through transcriptional profiling, we discovered a central role for TORC1 in orchestrating gene expression for ribosome biogenesis and cell metabolism in response to nutrients. Our studies characterized a role for the TORC1 pathway in governing filamentous differentiation of S. cerevisiae and other fungi in response to nutrient limitation. Employing a synthetic lethal genetic screen, we identified major TORC1 regulators including the Gtr GTPases conserved in humans (RAG GTPases) and established a strong link between TORC1 and the vesicular secretory system, congruent with our previous localization of TORC1 to the vacuolar membrane. In particular, we characterized a role for the class C-VPS complexes, which are major mediators of vesicular trafficking and protein sorting, in regulating TORC1 signaling. In summary these findings defined an endomembrane-associated nutrient sensing signaling cascade conserved from yeasts to humans. Rapamycin was approved by the FDA in 1999 as an immunosuppressive agent. Presently, rapamycin and derivatives are also FDA approved as novel chemotherapy agents for several types of solid organ tumors and as anti-scar agents in interventional cardiology, and may garner additional indications in aging and cognitive diseases and to boost vaccine effectiveness. Thus, the potential for significant and further advances in both basic science and medicine are outstanding.