UC San Diego

The ability of cells to maintain metabolic homeostasis in response to changes in nutrient availability is critical for cell survival. The mammalian target of rapamycin complex 1 (mTORC1) integrates various environmental stimuli to regulate cellular processes, including autophagy, cell growth, protein synthesis, and lipid metabolism. Of the various inputs to mTORC1, the amino acid sensing pathway is among the most potent. This thesis describes studies that aim to elucidate the molecular mechanisms by which cells regulate metabolic homeostasis in response to amino acids. In Chapter 1, we give a brief overview on the current knowledge about the mTOR signaling pathway and a short introduction about MAP kinases. In Chapter 2, we demonstrate a role for MAP4K3 in mTORC1 regulation. In MAP4K3 k.o. cells, we show that mTORC1 is unable to be activated in the presence of amino acids. We hypothesize that MAP4K3 is critical for the activation of mTORC1 through the inhibition of AMPK and TSC2, upstream inhibitors of mTORC1, in the presence of amino acids. In MAP4K3 k.o. cells, we show that there is more activated AMPK and less Rheb-dependent activation of mTORC1. Through these complex mechanisms, MAP4K3 emerges as a critical regulator of cellular homeostasis in response to amino acids via mTORC1 activity.