Regulation of autophagy by mTOR and amino acids

Amino acids are the molecular building blocks for proteins, which form the molecular framework of every cell. In addition, amino acids are also needed for the production of nucleotides and lipids to make DNA and membranes. Amino acids are essential biomolecules and without them cellular growth would not be possible. The protein mTOR (mammalian target of rapamycin) is a central signaling hub which promotes cellular growth. mTOR acts in two distinct multiprotein complexes, mTORC1 (mammalian target of rapamycin complex 1) and mTORC2. mTORC1 senses the availability of amino acids. When they are present, mTORC1 promotes anabolic, biosynthetic processes, and inhibits catabolic processes. One of these catabolic processes is autophagy. Deregulated autophagy has been linked with aging, and is a hallmark of age-related diseases, such as cancer. Even though autophagy per se is mechanistically well described, there is comparably little knowledge on the signaling networks which impinge on autophagy. In my PhD thesis I aimed to unravel and better characterize the signaling connections between amino acids, mTOR, and autophagy. I performed a screen, i. e. a large scale experiment in which I identified multiple kinases that regulate autophagy. I analyzed the amino acid-mTOR signaling network topology by a combined computational-experimental approach. In conclusion, my work provides novel insights into the mechanisms of amino acid-mediated mTOR- and autophagy regulation. mTOR and autophagy are important denominators of aging and age-related diseases including cancer. Therefore, my results contribute to the fundamental understanding of the molecular networks which govern aging processes and drive cancer cell growth