Rag GTPases

Gene/Protein · 25 studies in the Atlas · also known as Rag, Rag GTPase, RagA, RagB, RagC, RagD

Family of small GTPases that let mTORC1 sense amino acids by controlling its localization near its activator Rheb inside the cell.

The taxi that brings mTORC1 to the lysosome. A family of small molecular switches that let mTORC1 sense amino acids by controlling where inside the cell it's allowed to sit - specifically, whether it can get close enough to its activator Rheb.

Note the inversion: RagA/B is active when GTP-loaded, RagC/D when GDP-loaded. The Rags control mTORC1 *location*, not its catalytic activity.

TL;DR. Rag GTPases appears in 25 curated studies in Oliver's mTOR Atlas: 2 in animal models; 20 at the molecular level (cells, biochemistry, structure); 2 reviews; 1 preprint, not peer-reviewed. No study in people is recorded for it in the Atlas yet. It has 8 interactions in the curated pathway model.

In the pathway model

8 interactions in the curated mTOR pathway model (2 acting from Rag GTPases, 6 acting on it). Each row is a claim with the evidence behind it; the evidence code is the kind of study, not its quality.

Interaction	Mechanism	Evidence	Studies
Rag GTPases recruits mTORC1 mechanism: recruitment · this link in full · on the map table	The switched-on Rag proteins grab mTORC1 and drag it to the lysosome. This moves it into place; it doesn't turn it on by itself.The active Rag dimer grabs Raptor and physically drags mTORC1 to the lysosomal surface. This is a relocation, not an activation - the kinase is moved to where its activator waits. Holds under: Rag paralogues are not interchangeable: RagC/D sets substrate specificity downstream (RagD favors TFEB/TFE3 phosphorylation via tighter LAMTOR binding, while both Rags are involved for non-lysosomal substrates like S6K), and RagA/B sets the response to amino acid withdrawal (RagB-expressing cells keep mTORC1 lysosomal and active even when starved) — GOL2022. plausible in people, not shown directly · settled in the literature	A	SAN2008, SAN2010, LAW2018, GOL2022, EFE2012, CUI2025, NAR2011, KIM2008, ANA2019, KIM2012
Rag GTPases recruits TSC1/TSC2 mechanism: recruitment · this link in full · on the map table	Without amino acids, the Rags bring the TSC brake to the lysosome.When amino acids run out, the Rag GTPases also pull the TSC complex onto the lysosome, where it can switch Rheb off and help shut mTORC1 down. Holds under: Mammalian cell lines under acute amino-acid withdrawal; the contribution of this route in tissues is not established. Single study. plausible in people, not shown directly · emerging, few independent studies	M	DEM2014
FLCN / FNIP1/2 activates Rag GTPases mechanism: gap-activity · this link in full · on the map table	FLCN helps set the other half of the Rag pair (RagC/D) into its working shape: it makes RagC/D break down its bound GTP, the cell's energy-carrying molecule. So 'activates' here means it sets the state of that one half, not that it switches on every Rag. Its direct job is mainly to control one group of outputs (TFEB and TFE3) rather than the whole pathway, but in kidney and lung, losing FLCN can still end up over-activating mTORC1 through a feedback loop.FLCN-FNIP is the GAP for RagC/D: it makes RagC/D hydrolyse its bound GTP, which puts that half of the Rag dimer into the GDP-bound state. 'Activates' on this edge means exactly that: FLCN-FNIP sets the nucleotide state of RagC/D. It does not switch on every Rag. The dimer can hold mTORC1 only when both halves are in the right state (RagA/B GTP-bound and RagC/D GDP-bound), and other factors act on the RagA/B half. Its direct effect is SUBSTRATE-SPECIFIC: it gates TFEB and TFE3 phosphorylation, while canonical outputs like S6K1 and 4E-BP1 largely carry on without it in the short term. Holds under: FLCN's direct effect is substrate-specific: losing it blocks mTORC1 phosphorylation of TFEB/TFE3 while leaving S6K1 and 4E-BP1 largely intact in the short term (NAP2020). That is not the whole of Birt-Hogg-Dube, though. Constitutively active TFEB/TFE3 drive a feedback loop that hyperactivates mTORC1, and in kidney and lung that mTORC1 hyperactivation is itself a key driver of cyst and tumour formation (Di Malta 2023, EMBO Mol Med, PMID 36987696; Ferniani 2026, FER2026 in corpus; Cao 2026, JCI, PMID 41697734, 3 BHD patient lungs + mouse). So the regulation is tissue- and time-dependent, not a flat absence of hyperactivation. plausible in people, not shown directly · settled in the literature	M	LAW2019, SHE2019, NAP2020
GATOR1 inhibits Rag GTPases mechanism: gap-activity · this link in full · on the map table	GATOR1 forces the Rag proteins into their "off" shape, so they can no longer hold onto mTORC1.GATOR1 acts as a GAP: it forces RagA/B to hydrolyse GTP, flipping the Rag heterodimer into the inactive shape that cannot hold mTORC1. Holds under: Human cell biochemistry with cancer genomics (BAR2013) and a cryo-EM structure (SHE2018). GAP activity is shown on purified and cellular Rags; the cited studies do not test it in whole animals or in people. plausible in people, not shown directly · settled in the literature	M	BAR2013, SHE2018
Glutamine activates Rag GTPases mechanism: signal-relay · this link in full · on the map table	Glutamine can switch on mTORC1 partly just by being burned for fuel: burning it makes a molecule that helps the Rag proteins pull mTORC1 to the lysosome.Glutamine burned through glutaminolysis raises alpha-ketoglutarate, which promotes RagB GTP loading and mTORC1 translocation to the lysosome. This edge asserts the Rag-dependent route only. Holds under: Cell-type dependent, and deliberately narrow: the separate claim that glutamine can reach mTORC1 without the Rags is carried by its own edge rather than folded in here. not tested in people · emerging, few independent studies	M	DUR2012
LARS (leucyl-tRNA synthetase) activates Rag GTPases mechanism: gap-activity · this link in full · on the map table	In that model, this enzyme flips the other Rag protein into its working shape – an alternative route from leucine to the Rags.In this model LARS acts as a GAP for RagD, doing for the RagC/D half what FLCN does - an alternative route from leucine to the Rags. Holds under: Human cell biochemistry only, and cell-type dependence was never mapped. The reaction it claims - GAP activity on the RagC/D half - is the same reaction this Atlas assigns to FLCN, and the two assignments have never been reconciled head-to-head. Read together with LEU-LARS: if the upstream leucine-sensing claim does not hold, this edge loses its input. not tested in people · disputed: at least one study points the other way	M	HAN2012
Ragulator activates Rag GTPases mechanism: scaffolding · this link in full · on the map table	Ragulator anchors the Rag proteins to the lysosome and also helps flip them into their "on" shape, together with a second protein, SLC38A9. Both jobs are shown in biochemical experiments.Ragulator does two jobs on the Rags. It tethers the Rag heterodimer to the lysosomal surface, and it acts as an unusual exchange factor: first reported as a GEF for RagA/B (BAR2012), its exchange activity was later placed on RagC, where releasing GTP unlocks the inactive state (SHE2018B). Loading RagA with GTP is done by arginine-bound SLC38A9 (see SLC38A9-RAG). Holds under: Human cells, Drosophila and purified recombinant proteins (BAR2012, SAN2010, SHE2018B). The exchange activity was first assigned to RagA/B and later to RagC, so the exact step is still being refined. Whole-animal and human relevance are not tested here. plausible in people, not shown directly · settled in the literature	M	BAR2012, SAN2010, SHE2018B
SLC38A9 activates Rag GTPases mechanism: binding · this link in full · on the map table	SLC38A9 sits in the lysosome's wall, senses arginine inside, and then flips RagA into its "on" shape, telling the Rag proteins there's enough.SLC38A9 sits in the lysosomal membrane and reads arginine on the inside. Arginine-bound SLC38A9 acts as an exchange factor that loads RagA with GTP, switching the Rag dimer on (SHE2018B); it also pumps essential amino acids, including leucine, back out into the cytosol. Holds under: Mammalian cell studies and purified-protein work (REB2015, WAN2015, JUN2015, WYA2017, SHE2018B). Cell and biochemical evidence; whole-animal and human relevance are not tested here. plausible in people, not shown directly · settled in the literature	M	REB2015, WAN2015, JUN2015, WYA2017, SHE2018B

Evidence at a glance

Evidence	What it means	Studies
A	Animal model	2
M	Molecular — cells, biochemistry, structure	20
PP	Preprint, not peer-reviewed	1
R	Review — secondary literature, not a new result	2

No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.

Studies

Year	Evidence	Study
2026	A	Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis FER2026 Using kidney-specific mouse models that genetically uncouple mTORC1 activity from TFEB/TFE3 activity (Depdc5-KO, RagC-KO, and Flcn/RagC double-KO), the authors show mTORC1 hyperactivation -- not TFEB/TFE3 activation alone -- is the primary driver of kidney cystogenesis and tumorigenesis in Birt-Hogg-Dube and Tuberous Sclerosis Complex models. Constitutive TFEB/TFE3 activity further accelerates disease on top of mTORC1-driven pathology.
2012	A	Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival EFE2012 Rag-GTPase control of mTORC1 is essential for neonatal autophagy and survival to fasting.
2026	R	Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome CAO2026 Reframes Birt-Hogg-Dube (BHD) syndrome beyond the classic 'global mTORC1 hyperactivation' model: FLCN acts as a GAP for RagC/D, giving substrate-selective (not global) mTORC1 control. Biallelic FLCN loss drives kidney tumors via MiT/TFE nuclear accumulation, while haploinsufficiency alone is sufficient for lung and skin lesions -- resolving the 'mTORC1 paradox' via gene dosage and signaling timing. Narrative synthesis of human genetics and mouse mechanistic data.
2025	M	Structural basis for mTORC1 activation on the lysosomal membrane CUI2025 Resolves how mTORC1 flips from 'parked on the lysosome' to 'catalytically switched on'. Reconstituting the whole assembly on membranes from purified Rheb, Rag GTPases, Ragulator and mTORC1, cryo-EM shows the kinase reaches full activity only after two separate anchoring steps: Rag-Ragulator first pulls it to within about 100 angstroms of the membrane, then Rheb pulls it to within about 40 angstroms, and only when Raptor and mTOR itself also touch the membrane directly do the catalytic residues line up for full activity. Growth-factor input (via Rheb) and nutrient input (via the Rags) are shown converging on the same physical docking event rather than acting through separate switches. Boundary: reconstituted on synthetic membranes from purified components — a structural/biochemical model, not a measurement inside a living cell.
2023	M	Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex CUI2023 First structural view of how mTORC1 actually reaches TFEB to phosphorylate it: two full Rag-Ragulator complexes present a single TFEB molecule to the mTOR active site, one in the normal Raptor-docking arrangement and a second, non-canonical one that grips TFEB's own first helix. Mutating that grip point drives TFEB straight into the nucleus (turning on autophagy/lysosome genes) without disturbing where mTORC1 itself sits. Explains, at the level of atoms, why TFEB phosphorylation needs the tumour suppressor FLCN and the GDP-loaded state of RagC in a way the authors report for no other mTORC1 substrate. Boundary: cryo-EM of a complex reconstituted from purified human proteins — a static structural snapshot, not a live cell or a real-time measurement.
2023	R	The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease GOU2023 Authoritative review of the molecular basis of nutrient sensing and signalling by mTORC1 in disease.
2022	M	A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids GOL2022 The four mammalian Rag GTPase paralogues are not functionally interchangeable: RagC/D determines substrate specificity (RagD favors TFEB/TFE3 phosphorylation via tighter LAMTOR binding), while RagA/B determines the response to amino acid withdrawal (RagB-expressing cells keep mTORC1 lysosomal and active even upon starvation). Author correction issued 2023 (PMID 36536178, no change to conclusions).
2019	M	Structural basis for the docking of mTORC1 on the lysosomal surface ROG2019 3.2-angstrom cryo-EM structure of Raptor bound to Rag-Ragulator, showing how Raptor reads out the nutrient-dependent nucleotide state of the Rag GTPases: one part of Raptor senses RagA's nucleotide state, a separate 'claw' senses RagC's, and both have to be in the correct nutrient-signalling combination before Raptor is allowed to dock. Mutating the contact points blocks mTORC1 from reaching the lysosome and inhibits its signalling, which is the functional evidence behind the structural claim. Combined with a separate structure of mTORC1 bound to its activator Rheb, the paper builds a model of the complete, active mTORC1 sitting on the lysosome. Boundary: cryo-EM of a complex reconstituted from purified human proteins, not a live-cell measurement.
2019	M	Architecture of human Rag GTPase heterodimers and their complex with mTORC1 ANA2019 Structures of Rag GTPase heterodimers with mTORC1 explain nucleotide-state-dependent recruitment.
2018	M	Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes SHE2018 Cryo-EM structures of GATOR1 and GATOR1-Rag complexes reveal GAP and inhibitory-clamp mechanisms.
2018	M	Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms SHE2018B Ragulator and SLC38A9 each act as an unusual guanine-nucleotide exchange factor on the Rag heterodimer, and together they push it into its active state. Ragulator triggers GTP release from RagC, which unlocks the inactive configuration; arginine-bound SLC38A9 converts RagA from the GDP- to the GTP-loaded state. Boundary: purified proteins and cultured human cells. This is the biochemistry of the switch, not a measurement in tissue.
2017	M	Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex SUX2017 Hybrid structural model of the RagA/C-Ragulator mTORC1 activation complex.
2014	M	Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2 DEM2014 Amino-acid starvation recruits TSC2 to the lysosome to inhibit Rheb and TORC1.
2013	M	A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1 BAR2013 Found the OFF switch for amino acid signaling: the GATOR1 complex is a GAP that shuts the Rag GTPases (and thus mTORC1) down when amino acids run low, while GATOR2 opposes it. GATOR1 genes are mutated in cancers, making those tumors 'blind' to starvation and hypersensitive to rapamycin.
2013	M	Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1 PAN2013 The SEACIT complex is a GAP for the Rag/Gtr GTPases mediating amino-acid inhibition of TORC1.
2013	M	Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes MAR2013 The authors asked how TFEB reaches the lysosome, where mTORC1 phosphorylates it. In human cells, depleting Raptor inactivated mTORC1 and sent TFEB to the nucleus but did not stop TFEB binding lysosomes (82.5% of cells still showed lysosomal TFEB), whereas depleting the Rag GTPases or the Ragulator subunit p18 abolished it (under 4% of Rag-depleted cells kept the S211A mutant on lysosomes, against about 80% of controls). TFEB bound only active Rag heterodimers through its first 30 amino acids, and active Rags were enough to bring TFEB to lysosomes; TFEB mutants that could not bind Rags lost S211 phosphorylation and stayed in the nucleus. Endogenous TFEB accumulated in the nucleus after Torin1 or amino-acid starvation and moved back to the cytosol and lysosomes when amino acids were added again. Some MITF isoforms behaved the same way. Boundary: Human cell lines, mostly with overexpressed or mutant proteins; not tested in tissues or whole animals.
2012	M	SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling KIM2012 SH3BP4 negatively regulates amino-acid-Rag-GTPase-mTORC1 signalling.
2012	M	Leucyl-tRNA synthetase controls TORC1 via the EGO complex BON2012 In budding yeast, the leucyl-tRNA synthetase Cdc60 bound the Rag GTPase Gtr1, part of the EGO complex that activates TORC1, and this binding depended on leucine. The authors reported that the interaction was both necessary and sufficient to pass the leucine signal on to TORC1. When Cdc60 was busy editing wrongly charged tRNA(Leu), the interaction with Gtr1 was lost. The model is that TORC1 reads how well tRNA(Leu) is being charged as a stand-in for how much leucine the cell has. Together with Han et al. 2012 in human cells, it was one of the early papers to propose a tRNA synthetase as a leucine sensor upstream of the Rags. Boundary: Yeast only. The mammalian leucine sensor most widely accepted today is Sestrin2, and this yeast mechanism has not been reconciled with it. Drafted from the abstract only.
2011	M	mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase ZON2011 Showed amino acid sensing starts INSIDE the lysosome: amino acids accumulate in the lumen and the v-ATPase relays that signal outward ('inside-out') to Ragulator-Rag. A surprising twist on where the cell measures its nutrient status.
2011	M	Spatial coupling of mTOR and autophagy augments secretory phenotypes NAR2011 Protein synthesis and autophagic degradation are usually described as opposites that mTOR switches between, and this paper shows a compartment where the cell deliberately runs both at once. In senescent cells, autolysosomes and mTOR gather at one side of the Golgi (the TASCC), mTOR gets there in an amino-acid- and Rag-dependent way, and destroying that arrangement cuts interleukin-6/8 secretion. Boundary: cells, not organisms; it explains how the senescent secretory programme is fuelled, not whether blocking it helps an animal.
2010	M	Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids SAN2010 Established WHERE mTORC1 gets switched on: the lysosome surface. Identified Ragulator as the lysosomal dock that recruits the Rag GTPases and drags mTORC1 to the membrane where its activator Rheb lives. Amino acids work by controlling this translocation.
2010	M	Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner KAL2010 Metformin inhibits mTORC1 even in cells lacking AMPK or TSC1/TSC2, and the effect requires the Rag GTPases instead. Together with Foretz 2010 this places a large part of metformin's action outside the AMPK axis it is usually credited to.
2008	M	The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1 SAN2008 Identifies the Rag GTPase family as the missing link that lets mTORC1 sense amino acids by controlling whether mTOR is positioned near its activator Rheb.
2008	M	Regulation of TORC1 by Rag GTPases in nutrient response KIM2008 Rag GTPases mediate amino-acid signalling to TORC1 (parallel discovery to Sancak 2008).
2026	PP	ER-Lysosome Cholesterol Exchange Regulates Lysosomal Motility Through mTOR-Dependent LAMTOR1 Phosphorylation MUT2026 Identifies a new layer of control over mTORC1's lysosomal machinery: cholesterol exchange between the ER and lysosome regulates lysosome movement via mTOR-dependent phosphorylation of LAMTOR1, a core component of the Ragulator complex that anchors the Rag GTPases already in this Atlas.

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Barton, O. (2026). Rag GTPases [Entity page]. In Oliver's mTOR Atlas [Data set]. https://mtor-atlas.org/gene/rag-gtpases/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_gene_rag_gtpases,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}: Rag GTPases},
  howpublished = {Entity page in a data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/gene/rag-gtpases/},
  doi          = {10.5281/zenodo.22059963}
}

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