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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2016)

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.

    Cover page: The role of MAP4K3 in mTORC1 activation
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2023)
    mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1-AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1-AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell.
      Cover page: MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex.
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