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ArfGAP1 inhibits mTORC1 lysosomal localization and activation
Author(s) -
Meng Delong,
Yang Qianmei,
Melick Chase H,
Park Brenden C,
Hsieh TingSung,
Curukovic Adna,
Jeong MiHyeon,
Zhang Junmei,
James Nicholas G,
Jewell Jenna L
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020106412
Subject(s) - mtorc1 , biology , gtpase , microbiology and biotechnology , adp ribosylation factor , regulator , amino acid , subcellular localization , small gtpase , biochemistry , lysosome , cell , cytoplasm , golgi apparatus , signal transduction , gene , enzyme , pi3k/akt/mtor pathway
The mammalian target of rapamycin complex 1 (mTORC1) integrates nutrients, growth factors, stress, and energy status to regulate cell growth and metabolism. Amino acids promote mTORC1 lysosomal localization and subsequent activation. However, the subcellular location or interacting proteins of mTORC1 under amino acid‐deficient conditions is not completely understood. Here, we identify ADP‐ribosylation factor GTPase‐activating protein 1 (ArfGAP1) as a crucial regulator of mTORC1. ArfGAP1 interacts with mTORC1 in the absence of amino acids and inhibits mTORC1 lysosomal localization and activation. Mechanistically, the membrane curvature‐sensing amphipathic lipid packing sensor (ALPS) motifs that bind to vesicle membranes are crucial for ArfGAP1 to interact with and regulate mTORC1 activity. Importantly, ArfGAP1 represses cell growth through mTORC1 and is an independent prognostic factor for the overall survival of pancreatic cancer patients. Our study identifies ArfGAP1 as a critical regulator of mTORC1 that functions by preventing the lysosomal transport and activation of mTORC1, with potential for cancer therapeutics.