Loewith Lab

Research Projects

TOR controls growth

TOR, short for Target Of Rapamycin, is an atypical serine/threonine protein kinase which curiously resembles phosphatidylinositol lipid kinases. It plays a central role in orchestrating diverse aspects of cell metabolism and physiology (Wullschleger et al, Cell 2006 ). TOR was first identified genetically in S. cerevisiae as the molecular target of the natural product antifungal rapamycin (Box 1), but is broadly conserved in nearly all eukaryotes. Inside cells, rapamycin first interacts with a proline isomerase known as FKBP12 and this complex then binds and interferes with the ability of TOR to phosphorylate a subset of substrates. In 2002, we (Loewith et al., Mol Cell 2002 ) made the important discovery that TOR proteins operate in two distinct multiprotein complexes which we named TORC1 and TORC2 (mTORC1 and mTORC2 in mammalian cells). Rapamycin-sensitive TORC1 (Box 2) and rapamycin-insensitive TORC2 (Box 3) are independently regulated downstream of environmental as well as cell-intrinsic cues. In turn, each complex independently regulates distinct aspects of biomass production and turnover necessary to maintain cellular homeostasis (Eltschinger and Loewith, Trends in Cell Biol. 2016 ).

Presently, the lab uses state-of-the-art techniques in biochemistry, structure biology, and, in collaboration with groups in a National Centre for Competence in Research (NCCR ), chemical-biology and biophysics to determine how the kinase activities of TORC1 and TORC2 are regulated downstream of signals derived from metabolites and physical properties of membranes. These efforts are supported by an in-lab Orbitrap Fusion Tribrid mass spectrometer, a new, in-house, cryo-EM platform and generous funding from the Canton of Geneva, the Swiss National Science Foundation and the European Research Council.

Box 1. Rapamycin and Easter Island
Box 1. Rapamycin and Easter Island
Box 2. TORC1
Box 2. TOR Complex 1
Box 3. TORC2
Box 3. TOR Complex 2
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