Dissecting mTOR signalling
mTOR is an evolutionarily conserved serine threonine kinase known for its role in cell growth, proliferation and motility. It was initially discovered in the yeast Saccharomyces cerevisiae as two distinct multiprotein complexes, TORC1 and TORC2 that phosphorylate hundreds of proteins. It obtained its name because TORC1 can be inhibited by the bacterial secondary metabolite rapamycin. Mammalian TORC1 is a validated drug target in immunosuppression, cardiovascular procedures and oncology, but the molecular mechanisms that regulate its activity remain unknown. Scientists on the EU-funded TOR SIGNALLING (Growth control by the TOR signalling network) project hypothesised that similarly to TORC1, TORC2 may also be useful in the clinic. For this purpose, they set out to identify small molecule inhibitors of TORC2 signalling that could serve as therapeutic leads and tools to study mTOR function. To this end, scientists established a robust screening protocol in yeast capable of identifying drug-like small molecules that specifically inhibit TORC1 and/or TORC2. They successfully performed a high-throughput screen and identified two novel TORC1/2 inhibitors and several other compounds that affected TORC signalling upstream of the complexes. Using these compounds, the research team defined the TORC2-dependent phosphoproteome in yeast, thereby identifying the TORC2 target proteins. In addition, they discovered that TORC2 could serve as a major regulator of tensile homeostasis in the plasma membrane in eukaryotic cells. Overall, the results of the study provide novel insight into the function and mechanism of activity of TORC2 and these findings have clinical projections. The drug-like molecules could serve as pharmaceutical leads for inhibiting mTOR signalling in various diseases.
Keywords
mTOR signalling, yeast, TORC1, TORC2, phosphoproteome