Cell fate is influenced by the interplay of signals from the extracellular and intracellular environment. Studies over the years have revealed how the quality and quantity of signals triggered extracellular growth receptors mobilize intracellular signaling molecules leading to gene expression changes that dictate cell responses or fate. How such signals affect nutrient metabolism and how nutrient metabolites in turn control intracellular signaling, gene expression and ultimately cell fate remains poorly understood. A central signaling molecule that responds to nutrients and controls metabolism is mTOR. mTOR is an atypical Ser/Thr protein kinase that forms two protein complexes, mTORC1 and mTORC2. Numerous studies have focused on mTORC1, which is inhibited by the natural compound, rapamycin. mTORC1 is active in the presence of amino acids and promotes anabolic metabolism. In contrast to mTORC1, the regulation and functions of mTORC2 are poorly understood. In higher eukaryotes, mTORC2 is activated by growth factors such as insulin. Our project will elucidate how mTORC2 is involved in determining cell fate via its role in metabolic reprogramming during nutrient fluctuations. We will focus on how mTORC2 regulates the hexosamine biosynthetic pathway to control early thymocyte development. Our findings have implications for understanding how metabolism impacts cellular differentiation particularly in early T cell development. A deeper understanding of the regulation and functions of the mTOR complexes is needed for more effective therapeutic strategies against metabolic aberrations that occur during aging and diseases such as autoimmunity, diabetes and cancer.
The metabolism of nutrients is controlled by metabolic enzymes and signaling molecules. Our studies will elucidate how the protein complex, mTORC2, controls cell fate by metabolic reprogramming during nutrient fluctuations. Our studies will have impact in understanding how metabolic aberrations cause diseases such as autoimmunity, diabetes and cancer. !
