Rheb and Rags come together at the lysosome to activate mTORC1

Groenewoud, Marlous J.; Zwartkruis, Fried J.T.

doi:10.1042/bst20130037

Cited by 96PI3K/AKT/mTOR signaling in cancerAutophagy in Disease and TherapyCellular transport and secretion

Rheb and Rags come together at the lysosome to activate mTORC1

Groenewoud, Marlous J., Zwartkruis, Fried J.T.·2013·Biochemical Society Transactions

DOI 10.1042/bst20130037

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Abstract

mTORC1 (mammalian target of rampamycin complex 1) is a highly conserved protein complex regulating cell growth and metabolism via its kinase mTOR (mammalian target of rapamycin). The activity of mTOR is under the control of various GTPases, of which Rheb and the Rags play a central role. The presence of amino acids is a strict requirement for mTORC1 activity. The heterodimeric Rag GTPases localize mTORC1 to lysosomes by their amino-acid-dependent interaction with the lysosomal Ragulator complex. Rheb is also thought to reside on lysosomes to activate mTORC1. Rheb is responsive to growth factors, but, in conjunction with PLD1 (phospholipase D1), is also an integral part of the machinery that stimulates mTORC1 in response to amino acids. In the present article, we provide a brief overview of novel mechanisms by which amino acids affect the function of Rags. On the basis of existing literature, we postulate that Rheb is activated at the Golgi from where it will travel to lysosomes. Maturation of endosomes into lysosomes may be required to assure a continuous supply of GTP-bound Rheb for mTORC1 activation, which may help to drive the maturation process.

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Recruitment of (m)TORC1 to the lysosome is controlled predominantly in response to signals corresponding to the intracellular nutrient and energy state, whereas its activation once there is controlled by RhebGTP in response to a wide variety of external and survival signals feeding into a single point of control.
“Whereas recruitment of (m)TORC1 to the lysosome is controlled in response predominantly to signals corresponding to the intracellular nutrient and energy state, its activation once there is controlled by RhebGTP in response to a wide variety of external and survival signals feeding into a single point of control.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Groenewoud and Zwartkruis, 2013
The Rag and Rheb GTPases constitute a coincidence detector which cooperate synergistically to robustly induce mTORC1 activity and fail to do so when either is only singly activated under physiologic conditions.
“Together, these GTPases constitute a coincidence detector which cooperate synergistically to robustly induce mTORC1 activity and fail to do so when either is only singly activated under physiologic conditions (Durán and Hall, 2012; Groenewoud and Zwartkruis, 2013).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Groenewoud and Zwartkruis, 2013

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Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids
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Authors: Groenewoud, M. J., & Zwartkruis, F. J. T.
Affiliations: University Medical Center Utrecht (NL)
ORCID: Zwartkruis, Fried J.T.
Venue: Biochemical Society Transactions
Publisher: Portland Press Ltd.
Published: 2013-07-18
Volume: 41
Issue: 4
Pages: 951-955
ISSN: 0300-5127 (ISSN-L)
1470-8752
DOI: 10.1042/bst20130037
OpenAlex: W2127207520
Cited by: 96
References: 56
Citations by year: 2026: 3 · 2025: 5 · 2024: 6 · 2023: 9 · 2022: 7 · 2021: 10 · 2020: 12 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 6 · 2015: 10 · 2014: 5 · 2013: 1
FWCI: 0.69
Type: journal article
Language: en
Open access: closed
Locations: Biochemical Society Transactions (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords: Rheb, RAG, mTORC1, lysosomes, Ragulator complex, amino acid signaling, GTPase activation, phospholipase D1, Golgi apparatus, endosome maturation, cell growth regulation, cellular metabolism
MeSH terms: Ras Homolog Enriched in Brain Protein, Mechanistic Target of Rapamycin Complex 1, Amino Acids, Humans, Lysosomes, Neuropeptides, Monomeric GTP-Binding Proteins, Ephrin-A5, Multiprotein Complexes, TOR Serine-Threonine Kinases

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Rheb and Rags come together at the lysosome to activate mTORC1

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