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This growth-triggering system, known as the TOR pathway, is composed of a complex of proteins that respond to nutrient cues. Sabatini is working to identify TOR pathway components and study how they interact and work. His efforts to understand mammalian TOR at the cellular level have provided a new way to investigate the role nutrients and metabolism play in disease.
Rapamycin, an immunosuppressant that inhibits cell growth via the mTOR pathway, was first used to prevent organ rejection in kidney transplant patients. Today, it is employed as a drug as well as a research tool. As a graduate student and later as a Whitehead Fellow, Sabatini exposed cells to rapamycin and monitored its effect on TOR. Using this approach, Sabatini has identified several of the proteins that comprise the mammalian TOR complex.
Recently, Sabatini discovered a protein that stabilizes interactions between two other mTOR components. The balance between these protein components might be perturbed in human disease and could be a potential target for therapy. This seems to be the case in tumors caused by tuberous sclerosis (TS), a genetic disease that causes tuber-like growths throughout the body. In TS tumors the TOR pathway malfunctions, cell growth goes unchecked and cells become very large. Sabatini is screening various cancers to find others that result from dysfunctional mTOR activity and may respond to rapamycin therapy.
To study TOR, Sabatini needed to examine gene and protein function in thousands of living cells all at once, in real time. Because this was not possible with existing technology, Sabatini invented a cell microarray that allows his lab to study thousands of proteins simultaneously in a living cell and thus, evaluate the relationship between genes, proteins and disease.
Sabatini was appointed a Whitehead Fellow in 1997 after completing the MD/PhD program at Johns Hopkins University School of Medicine. Sabatini was named an Associate Member at Whitehead and an Assistant Professor in the biology department at MIT in 2002.
Selected Publications
Carpenter, A.E. and Sabatini, D.M. (2004). Systematic genome-wide screens of gene function. Nature Reviews Genetics. 5: 11-22.
Sarbassov, D., Ali, S.M., Kim, D.-H., Guertin, D.A., Latek, R.R., Erdjument-Bromage, H., Tempst, P., Sabatini, D.M. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current Biology, 14: 1296-1302.
Kim, D.-H., Sarbassov, D., Ali, S.M., Latek, R.R., Guntur, K.V.P., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (2003). G_L: a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between mTOR and raptor. Mol. Cell 11: 895-904.
Peng, T., Golub, T., and Sabatini, D.M. (2002). The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid or glucose deprivation. Mol. Cell. Bio. 22: 5575-5584.
Kim, D.-H., Sarbassov, D., Ali, S.M., King, J.E., Latek, R.R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D.M. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the growth machinery. Cell 110: 163-175.
Ziauddin, J. and Sabatini, D.M. (2001). Microarrays of cell expressing defined cDNAs. Nature 411:107-110.
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