Growth can be defined as the increase in the size of a cell or organism, due to a gain in mass caused by nutrient uptake and assimilation. Surprisingly, how growth is regulated was not well understood until quite recently. In his first talk, David Sabatini describes how insight into this question came from an unusual direction. The small molecule drug rapamycin was known to have anti-growth effects, but its intracellular target was not known. Sabatini explains how he purified and cloned the target of rapamycin from rat brain and showed that it was a protein kinase. This protein was named mTOR in mammals and was shown to be homologous to the TOR proteins in yeast. Sabatini and others went on to show that mTOR is at the heart of two large protein complexes, mTORC1 and mTORC2, that sense upstream signals such as nutrient levels, hormones, and growth factors and direct downstream effectors to build or breakdown resources as needed for cell growth and proliferation.
In his second talk, Sabatini explains that mTORC1 responds to many different upstream signals including a variety of growth factors, nutrients, and types of stress. How does mTORC1 sense all these different signals and integrate them to produce a response that regulates cell growth? Sabatini’s lab found that the first step in sensing nutrients such as amino acids is the movement of mTORC1 from a diffuse localization in the cytosol to the lysosomal surface. The lab then spent many years identifying the large number of proteins that regulate the movement of mTORC1 to the lysosome and allow it to sense nutrients and modulate the downstream processes that control cell growth. In particular, the lab identified several proteins that serve as direct sensors of metabolites or amino acids like leucine and arginine. Interestingly, mutations in several of the proteins in the nutrient sensing pathway upstream of mTORC1 are now known to cause human disease, including epilepsy. This suggests that modulation of mTOR, by inhibitors such as rapamycin, might provide a treatment for these conditions.
In his final talk, Sabatini focuses on a lysosomal membrane protein that his lab had found to interact with mTORC1 and to sense arginine levels inside the lysosome. In some cell types, the amino acids needed to build new proteins are not taken up as free amino acids but instead come from the breakdown of proteins in the lysosome. This led the lab to ask which arginine-rich proteins are being degraded in the lysosome, which led to the realization that ribosomal proteins are amongst the most arginine-rich proteins in mammalian cells. After many more experiments, they showed that mTORC1 regulates a balance between the biogenesis of ribosomes, and the breakdown of ribosomes (known as ribophagy), dependent on the nutritional state of the cell. Ribophagy seems to be particularly important for supplying the cell with nucleosides during nutrient starvation.
Dr. David M. Sabatini is a member of the Whitehead Institute for Biomedical Research, a professor of Biology at the Massachusetts Institute of Biology (MIT), an investigator of the Howard Hughes Medical Institute, a senior member of the Broad Institute of Harvard and MIT and a member of the Koch Institute for Integrative Cancer Research… Continue Reading