Claudio De Virgilio
Prof. Dr - Group Leader
All living cells are capable of exiting the normal cell cycle (proliferating state) and entering an alternative (resting) state termed quiescence or G0. Despite the fact that most eukaryotic cells - whether they exist as single cells or as part of a multicellular organism - spend most of their life in a quiescent state, relatively little is known about the regulatory mechanisms that control entry into or exit from such a state. The available body of data, nevertheless, indicates that disruption of G0-entry/exit control mechanisms is often associated with either cellular transformation (particularly in multicellular organisms), or dramatically reduced life span (of unicellular organisms). In this context, we study the mechanisms controlling entry into, survival in, and exit from quiescence in the unicellular, eukaryotic model organism S. cerevisiae. So far, several studies (including ours) have uncovered that the nutrient-regulated hub TORC1 orchestrates both entry into and exit from G0. Our research is therefore specifically focused on the elucidation of both the mechanisms that regulate TORC1 activity and the nature of the effectors that are regulated by TORC1.
Hyperactivation of mammalian TORC1 (mTORC1) has been implicated in a number of cancers and cancer predisposition hypertrophic syndromes. Identification of the conserved pathways that impinge on, or that are regulated by TORC1, are therefore likely to significantly contribute not only to our basic understanding of these fundamental processes, but also to the development of both diagnostic and therapeutic tools for the treatment of diseases associated with hyperactivated mTORC1.
Our current scientific projects are largely based on and logically extend from two key findings that we have made in the past. These include, firstly, our discovery of the vacuolar membrane-associated EGO (exit from rapamycin-induced growth arrest) complex (EGOC), which functions as a critical hub that relays amino acid signals to TORC1. The core of this complex contains a heterodimeric module consisting of Gtr1 and Gtr2, which belong to the Rag family of GTPases and which are asymmetrically loaded with guanine nucleotides. Interestingly, amino acids promote the GTP-bound state of Gtr1, which, combined with GDP-bound Gtr2, then interacts with and activates TORC1. Together with similar studies on Rag GTPases in higher eukaryotes, these findings shed light on an aspect of TORC1 control that has long remained a mystery and nucleated research that has developed into a rapidly evolving field. A second discovery that guided our more recent research was our finding that TORC1 antagonizes the function of the protein kinase Rim15, which is key for the induction of virtually all known aspects of the quiescence program in yeast. Notably, higher eukaryotic cells employ their Rim15-orthologous greatwall kinases (Gwl) to phosphorylate and activate the B55 type 2 protein phosphatase (PP2A-B55) inhibitors coined endosulfines, a process that ensures maintenance of high-level phosphorylation of cyclin B-CDK1 substrates during entry of cells into mitosis. Our current efforts are therefore specifically directed towards studies that explore the potential role of the Gwl pathway in cell cycle control in yeast.