Insights into the regulation of mTOR signaling and the consequences of pharmacological inhibition
Author(s)Thoreen, Carson Cornell
Massachusetts Institute of Technology. Dept. of Biology.
David M. Sabatini.
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Cells have evolved a highly tuned system for driving growth in response to the right cues. Permissive signals initiate a cascade of events that send nutrient transporters to the membrane, suppress apoptosis, boost protein synthesis, and adjust metabolic processes to fuel the cell's energy demands. Increases in cell growth are often coordinated with cell division, though the two programs can be decoupled. The TOR complexes, TORCI and TORC2, are central regulators of cell growth and share the serine/threonine TOR kinase as their catalytic domain. In mammals, the TORC2 homolog mTORC2 is activated by growth factors through the lipid kinase PI3K, and is a primary effector for many of its functions, including regulation of the proliferation and survival kinase Akt/PKB. Activation of PI3K also leads to activation of mTORC1. Unlike mTORC2, mTORC1 is equally dependent on nutrient availability, and connects to the protein translation machinery through its substrates S6K and 4E-BP1. Additionally, S6K can suppress insulin signaling, establishing a negative feedback loop to PI3K. Consistent with its role in cell growth, derangements in mTOR signaling are increasingly associated with cancer and, more surprisingly, metabolic diseases. In the work described here, we have investigated the mechanism through which insulin activates mTORC1 and identified the protein PRAS40 as a growth factor-regulated inhibitor and mTORC1 component. PRAS40 cooperates with rheb, an mTORC1 activator, to regulate growth factor signaling through the pathway. We have also developed a potent and selective mTORC1/2 small molecule inhibitor and used this to probe the role of mTOR signaling in tumor cell growth and proliferation. Through this, we have identified common genetic mutations that determine sensitivity to mTOR inhibition and suggest a novel therapeutic anticancer strategy.
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2008.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Dept. of Biology.
Massachusetts Institute of Technology