2. Academic Validation
  3. Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1

Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1

  • J Biol Chem. 2022 Jun;298(6):102030. doi: 10.1016/j.jbc.2022.102030.
Gwen R Buel 1,  Huy Q Dang 2,  John M Asara 3,  John Blenis 4,  Anders P Mutvei 5
Affiliations

Affiliations

  • 1 Programs in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA; Meyer Cancer Center and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
  • 2 Department of Immunology, Pathology and Genetics, Uppsala University, Uppsala, Sweden.
  • 3 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
  • 4 Meyer Cancer Center and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: jblenis@med.cornell.edu.
  • 5 Department of Immunology, Pathology and Genetics, Uppsala University, Uppsala, Sweden. Electronic address: anders.mutvei@igp.uu.se.
PMID: 35577075 DOI: 10.1016/j.jbc.2022.102030
Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and Amino acids, which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of Amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of Amino acids by canonical Autophagy or proteasomal degradation but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach.

Keywords

Akt; amino acid; mTORC1; signaling; starvation.

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