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The Rag GTPase Regulates the Dynamic Behavior of TSC Downstream of Both Amino Acid and Growth Factor Restriction.

Authors
  • Yang, Shu1
  • Zhang, Yingbiao1
  • Ting, Chun-Yuan1
  • Bettedi, Lucia1
  • Kim, Kuikwon1
  • Ghaniam, Elena1
  • Lilly, Mary A2
  • 1 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected]
Type
Published Article
Journal
Developmental cell
Publication Date
Sep 03, 2020
Identifiers
DOI: 10.1016/j.devcel.2020.08.006
PMID: 32898476
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The dysregulation of the metabolic regulator TOR complex I (TORC1) contributes to a wide array of human pathologies. Tuberous sclerosis complex (TSC) is a potent inhibitor of TORC1. Here, we demonstrate that the Rag GTPase acts in both the amino-acid-sensing and growth factor signaling pathways to control TORC1 activity through the regulation of TSC dynamics in HeLa cells and Drosophila. We find that TSC lysosomal-cytosolic exchange increases in response to both amino acid and growth factor restriction. Moreover, the rate of exchange mirrors TSC function, with depletions of the Rag GTPase blocking TSC lysosomal mobility and rescuing TORC1 activity. Finally, we show that the GATOR2 complex controls the phosphorylation of TSC2, which is essential for TSC exchange. Our data support the model that the amino acid and growth factor signaling pathways converge on the Rag GTPase to inhibit TORC1 activity through the regulation of TSC dynamics. Published by Elsevier Inc.

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