SNAT7 regulates mTORC1 via macropinocytosis.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Amino Acid Transport Systems, Neutral*/chemistry ; Amino Acid Transport Systems, Neutral*/genetics ; Amino Acid Transport Systems, Neutral*/metabolism ; Lysosomes*/enzymology ; Mechanistic Target of Rapamycin Complex 1*/metabolism ; Pinocytosis*; Asparagine/metabolism ; Glutamine/metabolism ; Humans ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Signal Transduction
    • Abstract:
      Mammalian target of rapamycin complex 1 (mTORC1) senses amino acids to control cell growth, metabolism, and autophagy. Some amino acids signal to mTORC1 through the Rag GTPase, whereas glutamine and asparagine activate mTORC1 through a Rag GTPase-independent pathway. Here, we show that the lysosomal glutamine and asparagine transporter SNAT7 activates mTORC1 after extracellular protein, such as albumin, is macropinocytosed. The N terminus of SNAT7 forms nutrient-sensitive interaction with mTORC1 and regulates mTORC1 activation independently of the Rag GTPases. Depletion of SNAT7 inhibits albumin-induced mTORC1 lysosomal localization and subsequent activation. Moreover, SNAT7 is essential to sustain KRAS-driven pancreatic cancer cell growth through mTORC1. Thus, SNAT7 links glutamine and asparagine signaling from extracellular protein to mTORC1 independently of the Rag GTPases and is required for macropinocytosis-mediated mTORC1 activation and pancreatic cancer cell growth.
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    • Grant Information:
      R01 GM129097 United States GM NIGMS NIH HHS; R35 CA220449 United States CA NCI NIH HHS; T32 GM008203 United States GM NIGMS NIH HHS
    • Contributed Indexing:
      Keywords: SNAT7; mTOR; macropinocytosis
    • Accession Number:
      0 (Amino Acid Transport Systems, Neutral)
      0RH81L854J (Glutamine)
      7006-34-0 (Asparagine)
      EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
    • Publication Date:
      Date Created: 20220513 Date Completed: 20220517 Latest Revision: 20240923
    • Publication Date:
      20240923
    • Accession Number:
      PMC9171778
    • Accession Number:
      10.1073/pnas.2123261119
    • Accession Number:
      35561222