Affinage

RRAGC

Ras-related GTP-binding protein C · UniProt Q9HB90

Length
399 aa
Mass
44.2 kDa
Annotated
2026-06-10
16 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RRAGC encodes RagC, a Ras-family GTPase that operates as a nucleotide-state-dependent switch controlling amino acid-driven activation of mTORC1 at the lysosomal/vacuolar membrane (PMID:26691987, PMID:25046117). Studies of the yeast ortholog Gtr2 establish that it functions as an obligate partner within the Rag/EGO heterodimer, directly binding the TORC1 subunit Kog1 and coupling TORC1 localization and activity to the Gtr1/Gtr2 nucleotide state (PMID:25046117, PMID:26609069), a configuration dependent on the EGO complex scaffold Ego3 (PMID:23123112). Conversion of RagC/Gtr2 to its GDP-bound state is driven by GAP complexes — the Lst4-Lst7 complex (functionally conserved with mammalian FLCN-FNIP) acts on Gtr2 at the vacuolar membrane upon amino acid refeeding to promote TORC1 activation (PMID:26387955), and the SEAC-EGOC supercomplex serves as the amino acid-sensing hub whose GAP activity is essential for TORC1 regulation [PMID:bio_10.1101_2024.10.05.616782]. In disease, recurrent somatic and de novo RRAGC missense mutations cluster around the GTP/GDP-binding site, increase binding to raptor (RPTOR), decrease interaction with the tumor suppressor FLCN, and render mTORC1 signaling constitutively active and resistant to amino acid deprivation (PMID:26691987, PMID:27267853, PMID:27234373, PMID:37057673), driving follicular lymphoma and a developmental disorder marked by increased cell size and dysregulated p70S6K and TFEB signaling (PMID:37057673). RRAGC raptor-dependent signaling is pharmacologically targetable, as RagC T90N-mutant cells are sensitized to raptor-depleting agents (PMID:37749558). Transcription of RRAGC is epigenetically repressed by EHMT2-mediated H3K9 dimethylation at the RRAGC locus in a ROS-dependent manner (PMID:32684241).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2012 Medium

    Placing RagC within an amino acid signaling cascade required defining where the Rag GTPases act relative to TORC1, answered by epistasis showing the Gtr1/Gtr2 heterodimer colocalizes with TORC1 at the vacuole downstream of Vam6 and upstream of TORC1.

    Evidence Genetic epistasis and colocalization imaging in fission yeast, with crystallography of the EGO scaffold Ego3

    PMID:22344254 PMID:23123112

    Open questions at the time
    • Direct nucleotide-state dependence of RagC not yet resolved
    • Mammalian RagC behavior inferred from yeast orthologs
  2. 2014 Medium

    How RagC engages the TORC1 machinery was clarified by showing Gtr2 directly binds the TORC1 subunit Kog1 and that GDP-bound Gtr1 (dependent on this binding) drives TORC1 inactivation and autophagy.

    Evidence Direct binding assay, genome-wide deletion epistasis, autophagy and Tor1 localization readouts in budding yeast

    PMID:25046117

    Open questions at the time
    • Single lab
    • Mammalian raptor-binding interface not directly mapped here
  3. 2015 High

    The mechanism setting RagC nucleotide state was established by identifying Lst4-Lst7 as a GAP for Gtr2 that converts it to GDP-bound, demonstrating GAP-driven RagC inactivation is required for amino acid-stimulated TORC1 activation.

    Evidence In vitro GAP assay, vacuolar localization imaging, glutamine refeeding and epistasis in yeast; functional parallels to TORC1 localization-coupled switching

    PMID:26387955 PMID:26609069

    Open questions at the time
    • Mammalian FLCN-FNIP GAP activity inferred by conservation rather than measured here
    • Kinetics of nucleotide cycling in vivo not quantified
  4. 2015 High

    The clinical relevance of RagC was established by finding recurrent somatic RRAGC mutations in follicular lymphoma that increase raptor binding and render mTORC1 resistant to amino acid deprivation, defining them as gain-of-function activators.

    Evidence Reciprocal Co-IP raptor-binding assays and mTORC1 activity readouts under amino acid deprivation in HEK293 cells

    PMID:26691987

    Open questions at the time
    • Structural basis of conformational locking not solved
    • In vivo tumorigenesis not directly demonstrated
  5. 2016 High

    The structural logic of oncogenic RRAGC mutations was defined by showing hotspot variants cluster at the nucleotide-binding site, simultaneously increase raptor binding and disrupt FLCN interaction, with yeast Gtr2 mutants phenocopying the effect.

    Evidence Co-IP, S6K phosphorylation western blots, yeast functional complementation, 3D modeling; independent de novo S75Y variant validated by overexpression and molecular dynamics

    PMID:27234373 PMID:27267853

    Open questions at the time
    • No experimental structure of mutant RagC-FLCN complex
    • Allosteric path linking nucleotide site to raptor interface not resolved
  6. 2016 Medium

    Membrane tethering of the Rag GTPases was addressed by showing Lam2 (LAMTOR2 homolog) physically interacts with Npr2 and Gtr1 and tethers GDP-bound Gtr1 to the vacuole to suppress TORC1.

    Evidence Co-IP, vacuolar localization imaging, Rps6 phosphorylation readout, and epistasis in fission yeast

    PMID:27227887

    Open questions at the time
    • Mammalian Ragulator-dependent tethering of RagC not directly tested here
    • Single lab
  7. 2020 Medium

    Regulation of RRAGC at the transcriptional level was established by showing EHMT2 directly represses RRAGC via H3K9 dimethylation at the locus in a ROS-dependent manner.

    Evidence ChIP for EHMT2 occupancy, RNA-seq, sgRNA loss-of-function, and ROS-scavenger treatment in hepatocellular carcinoma cells

    PMID:32684241

    Open questions at the time
    • Functional consequence of RRAGC derepression on mTORC1 not quantified here
    • Single lab
  8. 2023 Medium

    Germline RRAGC variation as a developmental disease mechanism was established by showing de novo missense variants constitutively activate mTORC1 with increased cell size and decoupling of mTOR localization from metabolic state; raptor was confirmed as the actionable downstream node.

    Evidence Patient-derived fibroblasts and HEK293 models, p70S6K/TFEB readouts, localization imaging; raptor-depleting cardamonin sensitivity with shRNA epistasis and xenograft validation

    PMID:37057673 PMID:37749558

    Open questions at the time
    • Single lab for each study
    • Long-term organismal consequences not modeled
  9. 2024 High

    The architecture of the amino acid-sensing hub was resolved by a cryo-EM structure of the SEAC-EGOC supercomplex, showing SEAC binds active GTP-loaded EGOC and that its GAP activity is essential for amino acid-dependent TORC1 regulation.

    Evidence Cryo-EM structure determination, in vitro GAP assay, and SEAC subunit deletion epistasis in yeast (preprint)

    PMID:bio_10.1101_2024.10.05.616782

    Open questions at the time
    • Mammalian equivalent supercomplex not structurally resolved
    • Preprint, not peer-reviewed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How oncogenic and developmental RRAGC mutations structurally lock the heterodimer into a raptor-competent, FLCN-resistant conformation, and whether RagC has Gtr1-independent roles, remain unresolved.
  • No experimental structure of mutant mammalian RagC heterodimer with raptor or FLCN
  • Gtr2-specific Golgi/exocytic function (idx 13) lacks direct biochemical mechanism
  • Whether transcriptional repression of RRAGC alters tumor mTORC1 output is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0003924 GTPase activity 2
Localization
GO:0005773 vacuole 4 GO:0005886 plasma membrane 3
Pathway
R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2
Partners
EHMT2FLCNKOG1LST4LST7RPTORRRAGA
Complex memberships
EGO complex (EGOC)Rag GTPase heterodimer (RagA/B-RagC)TORC1/mTORC1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Recurrent somatic RRAGC mutations in follicular lymphoma increase raptor (RPTOR) binding while rendering mTORC1 signaling resistant to amino acid deprivation, establishing these variants as gain-of-function activators of mTORC1. Co-immunoprecipitation (raptor binding assay), mTORC1 activity assays under amino acid deprivation in stable HEK293 cells expressing mutant RRAGC Nature genetics High 26691987
2016 Follicular lymphoma-associated RRAGC hotspot mutations cluster around the GTP/GDP-binding site, increase binding to RPTOR (raptor), substantially decrease interaction with the tumor suppressor FLCN (folliculin), and elevate mTOR signaling (S6K phosphorylation) in a leucine-independent manner; equivalent Gtr2 mutations in yeast phenocopy these effects. Co-immunoprecipitation, western blot (S6K phosphorylation), stable retroviral and lentiviral cell lines, yeast functional complementation, 3D protein modeling Clinical cancer research High 27267853
2016 A de novo S75Y missense mutation in RRAGC renders AD293 cells partially insensitive to amino acid deprivation, resulting in increased mTORC1 signaling compared to wild-type RagC, establishing this as a gain-of-function mutation. Overexpression of RagC(S75Y) in AD293 cells, mTORC1 activity assay under amino acid deprivation, in silico molecular dynamics simulation predicting disruption of GDP ligand interactions Human genetics Medium 27234373
2023 De novo RRAGC missense variants (Thr90Asn, Pro118Leu, Trp115Arg) constitutively activate mTORC1: patient-derived fibroblasts with Thr90Asn show increased cell size, dysregulated p70S6K and TFEB signaling, and decoupling of mTOR subcellular localization from metabolic state; all three variants confirmed in HEK293 cell model. Patient-derived fibroblast studies, HEK293 cell overexpression model, western blot (p70S6K phosphorylation), TFEB signaling assay, mTOR subcellular localization imaging Genetics in medicine Medium 37057673
2023 Cardamonin disrupts mTOR-Raptor complex interactions by reducing Raptor protein levels; RRAGC T90N-mutant cells show elevated mTORC1 activity and increased sensitivity to cardamonin; Raptor knockdown abolishes cardamonin's inhibitory effects, placing Raptor downstream of RRAGC in the mTORC1 pathway. Co-immunoprecipitation (mTOR-Raptor-RagC interactions), lentiviral overexpression of RagC WT and T90N, shRNA Raptor knockdown, western blot (mTOR and S6K1 phosphorylation), CCK-8 viability assay, xenograft mouse model BMC complementary medicine and therapies Medium 37749558
2015 In yeast, Lst4-Lst7 functions as a GAP complex for Gtr2 (the RRAGC ortholog) and localizes to the vacuolar membrane in amino acid-starved cells; amino acid refeeding (glutamine) transiently stimulates Lst4-Lst7 to act on Gtr2, promoting TORC1 activation, demonstrating that GAP-mediated conversion of Gtr2 to GDP-bound state is required for TORC1 activation. Biochemical GAP assay, vacuolar membrane localization imaging, genetic epistasis in yeast, amino acid stimulation experiments Cell reports High 26387955
2014 In yeast, Gtr2 (RRAGC ortholog) directly binds the TORC1 subunit Kog1; GDP-bound Gtr1 (requiring Gtr2-Kog1 direct binding) is required for TORC1 inactivation and autophagy induction; Npr2-Npr3 act upstream of Gtr1-Gtr2 to regulate these nucleotide states. Genetic epistasis (genome-wide deletion screen, double mutant analysis), direct binding assay (Gtr2-Kog1), autophagy assay, Tor1 localization imaging Autophagy Medium 25046117
2015 In budding yeast, TORC1 localization to vacuolar puncta is facilitated by direct binding to Gtr2 (RRAGC ortholog) and is coupled to TORC1 inactivation; when Gtr1 is GDP-bound, TORC1-Gtr1/2-Ego complex relocalizes to puncta, whereas GTP-Gtr1 promotes vacuolar membrane localization and TORC1 activation. Fluorescence microscopy (colocalization), genetic mutant analysis (GTP/GDP-locked Gtr1), TORC1 activity assays Molecular biology of the cell Medium 26609069
2012 In fission yeast, Gtr1 and Gtr2 (RRAGC ortholog) colocalize with TORC1 at vacuoles and function downstream of Vam6 and upstream of TORC1 in the amino acid signaling pathway, as established by epistasis analysis. Genetic epistasis analysis, colocalization imaging, growth and mating/sporulation phenotypic assays in S. pombe Journal of cell science Medium 22344254
2012 Crystal structure of Ego3 reveals a homodimeric fold similar to Gtr1-Gtr2 C-terminal domains; structural and genetic data identify a binding site for Gtr1-Gtr2 on Ego3, and the Ego3 dimer conformation is essential for EGO complex integrity and TORC1 signaling. X-ray crystallography, structure-guided mutagenesis, genetic complementation in yeast Structure High 23123112
2016 In fission yeast, loss of Lam2 (LAMTOR2 homolog) or Npr2-Npr3 diminishes vacuolar localization and protein levels of Gtr1 and Gtr2; Lam2 physically interacts with Npr2 and Gtr1 and functions as a tether for GDP-bound Gtr1 to the vacuolar membrane, thereby suppressing TORC1 activity. Genetic epistasis, co-immunoprecipitation (Lam2-Npr2-Gtr1 interaction), fluorescence microscopy (vacuolar localization), TORC1 activity assay (Rps6 phosphorylation) PloS one Medium 27227887
2020 EHMT2 (GLP/G9a) directly suppresses RRAGC gene expression in hepatocellular carcinoma cells through H3K9 dimethylation at the RRAGC locus in a ROS-dependent manner, as demonstrated by ChIP assay showing EHMT2 occupancy and upregulation of RRAGC protein upon EHMT2 inhibition. ChIP assay, RNA sequencing, sgRNA-mediated loss-of-function, proteomic analysis, ROS scavenger (NAC) treatment BMB reports Medium 32684241
2024 Cryo-EM structure of the yeast SEAC-EGOC supercomplex reveals that a single SEAC binds two EGOC molecules via SEACIT exclusively when Gtr1 (RagA/B ortholog) is GTP-loaded (active EGOC); SEAC functions as a GAP for Gtr1, and its GAP activity is essential for TORC1 regulation by amino acids; loss of GAP activity phenocopies loss of Gtr1-Gtr2, establishing the SEAC-EGOC as the amino acid-sensing hub. Cryo-electron microscopy structure determination, in vitro GAP assay, genetic loss-of-function (SEAC subunit deletions), TORC1 activity assay bioRxivpreprint High bio_10.1101_2024.10.05.616782
2009 In budding yeast, overexpression of Gtr2 (but not its heterodimeric partner Gtr1) specifically suppresses both the toxicity and secretory defect caused by small molecules that perturb late exocytic transport, indicating Gtr2 can regulate a late exocytic pathway at the Golgi independently of Gtr1. Chemical-genetic screen, overexpression suppression assay, secretory cargo accumulation assay Eukaryotic cell Low 19897736

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nature genetics 162 26691987
2015 Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2. Cell reports 109 26387955
2015 Dynamic relocation of the TORC1-Gtr1/2-Ego1/2/3 complex is regulated by Gtr1 and Gtr2. Molecular biology of the cell 62 26609069
2014 Reciprocal conversion of Gtr1 and Gtr2 nucleotide-binding states by Npr2-Npr3 inactivates TORC1 and induces autophagy. Autophagy 61 25046117
2012 The Vam6 and Gtr1-Gtr2 pathway activates TORC1 in response to amino acids in fission yeast. Journal of cell science 54 22344254
2012 Ego3 functions as a homodimer to mediate the interaction between Gtr1-Gtr2 and Ego1 in the ego complex to activate TORC1. Structure (London, England : 1993) 52 23123112
2016 Recurrent Mutations in the MTOR Regulator RRAGC in Follicular Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research 38 27267853
2016 De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy. Human genetics 31 27234373
2021 GTR1 and GTR2 transporters differentially regulate tissue-specific glucosinolate contents and defence responses in the oilseed crop Brassica juncea. Plant, cell & environment 22 33908644
2022 Ablation of glucosinolate accumulation in the oil crop Camelina sativa by targeted mutagenesis of genes encoding the transporters GTR1 and GTR2 and regulators of biosynthesis MYB28 and MYB29. Plant biotechnology journal 18 36165983
2023 Targeted editing of multiple homologues of GTR1 and GTR2 genes provides the ideal low-seed, high-leaf glucosinolate oilseed mustard with uncompromised defence and yield. Plant biotechnology journal 16 37539488
2020 Euchromatin histone methyltransferase II (EHMT2) regulates the expression of ras-related GTP binding C (RRAGC) protein. BMB reports 9 32684241
2016 The Loss of Lam2 and Npr2-Npr3 Diminishes the Vacuolar Localization of Gtr1-Gtr2 and Disinhibits TORC1 Activity in Fission Yeast. PloS one 9 27227887
2023 De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood. Genetics in medicine : official journal of the American College of Medical Genetics 6 37057673
2009 A chemical genetic screen for modulators of exocytic transport identifies inhibitors of a transport mechanism linked to GTR2 function. Eukaryotic cell 6 19897736
2023 Raptor mediates the selective inhibitory effect of cardamonin on RRAGC-mutant B cell lymphoma. BMC complementary medicine and therapies 2 37749558

Missed literature

Know a paper Affinage missed for RRAGC? Flag it for the maintainers and the community.

No submissions yet.