@article{0b503416edd6471ca7baf2a3c6e6a865,
title = "ArfGAP1 inhibits mTORC1 lysosomal localization and activation",
abstract = "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.",
keywords = "ArfGAP1, amino acids, lysosome, mTORC1, vesicle trafficking",
author = "Delong Meng and Qianmei Yang and Melick, {Chase H.} and Park, {Brenden C.} and Hsieh, {Ting Sung} and Adna Curukovic and Jeong, {Mi Hyeon} and Junmei Zhang and James, {Nicholas G.} and Jewell, {Jenna L.}",
note = "Funding Information: We thank Dr. Joseph Albanesi for valuable suggestions. We are grateful to all members of the Jewell laboratory for insightful discussions. We thank Gina Park for help with the GST protein purification. We thank Huyen Nguyen, Teresa Yoon, and Greg Urquhart for technical help. We thank Krzysztof Gonciarz from the MOSAIC group at Max Planck Institute of Molecular Cell Biology and Genetics (MPI‐CBG) for technical help for the use of the Squassh segmentation algorithm. This work was supported by grants from Cancer Prevention Research Institute of Texas (CPRIT) Scholar Recruitment of First‐Time, Tenure‐Track Faculty Member (RR150032), Cancer Prevention Research Institute of Texas (CPRIT) High‐Impact/High‐Risk Research Award (RP160713), The Welch Foundation (I‐1927‐20170325 & I‐1927‐20200401), 2017 UT Southwestern President{\textquoteright}s Research Council Distinguished Researcher Award, American Cancer Society Research Scholar Grant (133894‐RSG‐19‐162‐01‐TBE), National Institutes of Health (R01GM129097‐01) to J.L.J., and (P20 GM113134/GM/NIGMS and R01 GM123048/GM/NIGMS) to N.J. Publisher Copyright: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license",
year = "2021",
month = jun,
day = "15",
doi = "10.15252/embj.2020106412",
language = "English (US)",
volume = "40",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "12",
}