Nutrient sensing and control of cell growth; relevant to immunosuppressive, anticancer, and fungicidal drug action.
Our lab focuses on elucidating the mechanisms of activation and signaling of the Tor kinases, which are central components of a ubiquitously conserved signal transduction cascade that controls cell growth in response to nutrients and growth factors. Tor was discovered in S. cerevisiae as the target of the potent immunosuppressive and anticancer drug rapamycin. Rapamycin has widespread applications in several clinical arenas including organ transplantation, cancer chemotherapy, and cardiology. We employed yeast to characterize the genetic synthetic interaction network of TOR1. These studies uncovered a novel role for the endomembrane vesicular trafficking system in regulating Tor complex 1 (TORC1) signaling. We found that cell growth is compromised or abolish when mutations in different protein complexes including the class C VPS, preautophagosomal (PAS), and EGO (EGOC) involved in vesicular trafficking and protein sorting are combined with a mutation of the nonessential Tor1 kinase. Interestingly, the EGOC and orthologs of its GTPase subunits (the Rag proteins) have been recently implicated in amino acid-dependent TORC1 activation in yeast, mammalian, and insect cells.
Current studies focus on characterizing the vesicular trafficking system roles in TORC1 signaling and to elucidate the molecular mechanism by which amino acid signals evoke TORC1 activation. TORC1 pathway components and the EGOC are localized to vacuolar membranes. Our hypothesis is that this endomembrane network serves as a platform to facilitate molecular interactions that activate and enable TORC1 signaling. Similar to yeast TORC1, the mammalian mTORC1 ortholog targeted by rapamycin and its analogs in the treatment of multiple cancer malignancies has been localized to endomembranes. Thus, our studies will continue to reveal fundamental basic and conserved aspects of Tor signaling that could serve as a guide to pharmacological intervention in select mTor pathway defects in oncology.