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▶Subject: New Biology of Amino Acids and Its Therapeutic Potential
▶Speaker: Prof. Jung Min Han (Yonsei University)
▶Place: Auditorium(1F),Postech Biotech Center
Amino acids are required for the activation of the mammalian target of rapamycin (mTOR) kinase which is the target of the anti-cancer drug rapalogs (rapamycin derivatives) and the central component of a nutrient- and hormone-sensitive signaling pathway that regulate protein translation, cell size, cell growth, and autophagy. The molecular mechanisms of mTORC1 regulation by growth factors and cellular energy status have been extensively studied. However, the mechanism of mTORC1 activation by amino acids is largely unknown, although amino acid is the most potent activator of mTORC1. To elucidate how amino acid availability is wired to the regulation of translation and autophagy through mTORC1 pathway has been a major issue in this field for a long time. Among amino acids, intracellular leucine is recognized as a major signal nutrient that regulates mTORC1. However, how intracellular leucine is sensed for mTORC1 still remains to be solved. In this seminar, I will show that leucyl-tRNA synthetase (LRS) is an mTORC1-associated protein and plays an essential role as a leucine sensor for mTORC1 signaling. Ablation of leucine binding ability in leucyl-tRNA synthetase desensitizes the mTORC1 pathway to amino acids. Among the components of mTORC1, LRS directly interacts with Rag GTPase in amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. These results suggest that leucyl-tRNA synthetase is not only a housekeeping enzyme to link genetic codes to amino acids for protein synthesis, but also an intracellular amino acid sensor for mTORC1 signaling. By these dual mechanisms, leucyl-tRNA synthetase can coordinate translation via catalytic and non-catalytic routes. This work also suggests new therapeutic potential of LRS in cancer. I will briefly introduce the current status of LRS-targeting anti-cancer drug development.
▶Inquiry: Prof. Sungho Ryu(279-2292)