GATOR1

Pathway/Complex · 7 studies in the Atlas

Negative regulator of the Rag GTPases (a GAP); switches mTORC1 OFF when amino acids are scarce. Tumor suppressor - mutated in some cancers.

The switch-off machine for the Rags. The main 'off switch' for mTORC1 in the amino-acid sensing system - it acts on the Rag GTPases to shut mTORC1 down when nutrients run low. It's a tumor suppressor, and it's found mutated in some cancers.

DEPDC5 loss causes focal epilepsy – a human phenotype that establishes GATOR1's physiological relevance beyond cell lines.

TL;DR. GATOR1 appears in 7 curated studies in Oliver's mTOR Atlas: 1 in people (1 human study); 2 in animal models; 4 at the molecular level (cells, biochemistry, structure). It has 4 interactions in the curated pathway model.

In the pathway model

4 interactions in the curated mTOR pathway model (1 acting from GATOR1, 3 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
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. 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
GATOR2 inhibits GATOR1 mechanism: binding · this link in full · on the map table	Everyone agrees GATOR2 holds GATOR1 back when amino acids are around. Exactly how it does it is not settled by the work this Atlas holds, and the gap is left visible on purpose. Released GATOR2 suppresses GATOR1 - a double negative. Two brakes in series is why the sensors can flip mTORC1 on so sharply. Released GATOR2 suppresses GATOR1 - a double negative. Two brakes in series is why the sensors can flip mTORC1 on so sharply. Holds under: The epistasis is solid. VAL2022 resolved GATOR2's architecture by cryo-EM - a 1.1 MDa cage - and mapped where the sensors dock, but exactly how GATOR2 suppresses GATOR1's GAP activity is still not settled. plausible in people, not shown directly · emerging, few independent studies	M	BAR2013, PAR2014, VAL2022
KICSTOR required-for GATOR1 mechanism: recruitment · this link in full · on the map table	KICSTOR works like a docking clamp that holds GATOR1 in place on the lysosome; without it, GATOR1 can't reach its target. KICSTOR is the dock that holds GATOR1 on the lysosomal surface. Without it, GATOR1 cannot reach its target and nutrient control of mTORC1 is lost. KICSTOR is the dock that holds GATOR1 on the lysosomal surface. Without it, GATOR1 cannot reach its target and nutrient control of mTORC1 is lost. Holds under: Mammalian cell genetics (WOL2017, PEN2017). The dependency is shown in cultured cells; whole-animal and human relevance are not tested in the cited work. plausible in people, not shown directly · settled in the literature	M	WOL2017, PEN2017
SAMTOR activates GATOR1 mechanism: binding · this link in full · on the map table	When methionine is low, SAMTOR teams up with GATOR1 to help keep mTORC1 switched off. Methionine-starved SAMTOR binds the GATOR1-KICSTOR complex and helps it keep mTORC1 off. Methionine-starved SAMTOR binds the GATOR1-KICSTOR complex and helps it keep mTORC1 off. Holds under: One biochemical study in human cells (GU2017). A single study in cell culture; the consensus is emerging, not settled. plausible in people, not shown directly · emerging, few independent studies	M	GU2017

Evidence at a glance

Evidence	What it means	Studies
H	Human study	1
A	Animal model	2
M	Molecular — cells, biochemistry, structure	4

Studies

Year	Evidence	Study
2013	H	Mutations in DEPDC5 cause familial focal epilepsy with variable foci DIB2013B Exome sequencing and linkage in families with autosomal dominant familial focal epilepsy with variable foci identified loss-of-function mutations in DEPDC5, a GATOR1 subunit, in 5 of 6 additional published large families and in roughly 12% (10/82) of smaller focal-epilepsy families. This is the human genetic anchor for GATOR1's physiological importance: it supports that loss of a GATOR1 subunit produces a human phenotype. Observational genetic association within families, not an interventional study, and the paper carries no mTORC1 readout of its own - the link to the pathway rests on the molecular work (BAR2013, SHE2018), not on this 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.
2026	A	Constitutive mTORC1 Activation in Skeletal Muscle Increases Inflammation but is not Sufficient to Impair Glucose Tolerance. MARCHANT2026 Constitutive mTORC1 activation in mouse skeletal muscle (via GATOR1 complex KO) increases inflammatory markers but is not sufficient to impair glucose tolerance, indicating that additional metabolic inputs beyond muscle mTORC1 hyperactivation are required to drive glucose intolerance.
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.
2017	M	SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway GU2017 Extended nutrient sensing beyond amino acids to METABOLITES: SAMTOR reads S-adenosylmethionine (SAM), the cell's methyl-donor currency, linking methionine and one-carbon metabolism to mTORC1. Relevant to why methionine restriction affects aging.
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.

Related entities

mTORC1 6 Rag GTPases 4 TFEB 1 GATOR2 1 SAMTOR 1 Tuberous sclerosis complex 1 S-adenosylmethionine (SAM) 1 Insulin resistance 1 FLCN / FNIP1/2 1 Tumor growth 1

Cite this page

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Barton, O. (2026). GATOR1 [Entity page]. In Oliver's mTOR Atlas [Data set]. https://mtor-atlas.org/complex/gator1/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_complex_gator1,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}: GATOR1},
  howpublished = {Entity page in a data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/complex/gator1/},
  doi          = {10.5281/zenodo.22059963}
}

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