David Sabatini (Whitehead, MIT, HHMI) 2: Regulation of mTORC1 by Nutrients

David Sabatini (Whitehead, MIT, HHMI) 2: Regulation of mTORC1 by Nutrients

Recording date: 28/11/2018
Viewed: 2 times

https://www.ibiology.org/cell-biology/mtor-regulation David Sabatini outlines the critical role of mTOR in the regulation of growth. mTOR senses nutrient levels, growth factors and other signals and integrates a response to regulate cell growth. (Part 2 of 3) 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. Speaker Biography: 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 at MIT. His lab is interested in the regulation of growth and metabolism in mammals, with a focus on the critical mTOR pathway. Research from Sabatini’s lab has led to a better understanding of the role of the mTOR pathway in diseases such as cancer and diabetes, as well as in aging. Sabatini received his undergraduate degree in biology from Brown University. As a MD/PhD student at Johns Hopkins University School of Medicine, he did his first experiments on rapamycin and mTOR in the lab of Solomon H. Snyder. After completing his MD/PhD in 1997, Sabatini started his own lab as a Whitehead fellow at the Whitehead Institute. In 2002, he became a member of the Whitehead Institute and a faculty member at MIT. Sabatini’s groundbreaking work has been recognized with numerous awards and honors including the National Academy of Science Award in Molecular Biology (2014), the Dickson Prize in Medicine (2017), the Lurie Prize in Biomedical Sciences (2017), and the Switzer Prize (2018). Sabatini was elected to the National Academy of Sciences in 2016. Learn more about the research being done in Sabatini’s lab here: http://sabatinilab.wi.mit.edu and here: https://www.hhmi.org/scientists/david-m-sabatini

David Sabatini (Whitehead Institute, Massachusetts Institute of Technology, and Howard Hughes Medical Institute)


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