RRAGC

RRAGC encodes the Rag GTPase C subunit, which heterodimerizes with RagA/B to form a nucleotide-state-dependent switch that recruits mTORC1 to the lysosomal membrane in response to amino acid sufficiency. In the mTORC1-activating configuration, RagC is GDP-loaded—a state promoted by the folliculin (FLCN)-FNIP complex acting as a GTPase-activating protein—and directly binds the mTORC1 subunit Raptor to enable lysosomal recruitment and downstream phosphorylation of S6K and TFEB (PMID:26387955, PMID:25046117, PMID:26691987). Recurrent somatic missense mutations in RRAGC found in follicular lymphoma increase Raptor binding and decrease FLCN interaction, rendering mTORC1 constitutively active independently of amino acid availability (PMID:26691987, PMID:27267853). De novo germline RRAGC missense variants cause a developmental disorder characterized by constitutive mTORC1 overactivation, increased cell size, and dysregulated TFEB signaling (PMID:37057673).

1. 2012 Medium

   Establishing that the RagC ortholog (Gtr2) functions within the amino acid–TORC1 signaling axis at the vacuolar membrane answered where in the pathway this GTPase operates, positioning it downstream of Vam6 and upstream of TORC1.

   Evidence Genetic epistasis and co-localization microscopy in fission yeast

   PMID:22344254

   Open questions at the time

   • Mammalian validation not shown
   • Direct binding to TORC1 not demonstrated in this system
   • GAP identity for Gtr2 not identified
2. 2014 High

   Demonstrating that GDP-bound Gtr2 directly binds the TORC1 subunit Kog1 (Raptor ortholog) established the physical basis for how the nucleotide state of RagC controls TORC1 recruitment and activity, including autophagic induction upon TORC1 inactivation.

   Evidence Reciprocal Co-IP of Gtr2–Kog1, genome-wide yeast deletion screen, GTP/GDP-locked mutant epistasis, and autophagy assays

   PMID:25046117

   Open questions at the time

   • Mammalian Raptor–RagC direct binding not yet shown biochemically
   • Structural basis of interaction unknown
3. 2015 High

   Identification of the Lst4-Lst7 complex as a GAP for Gtr2 revealed that a dedicated GAP converts RagC to its GDP-loaded (mTORC1-activating) state upon amino acid refeeding, paralleling the mammalian FLCN-FNIP complex and explaining how nutrient signals are transmitted through RagC nucleotide cycling.

   Evidence GAP activity assays, vacuolar localization, amino acid refeeding in yeast, genetic epistasis

   PMID:26387955

   Open questions at the time

   • Mammalian FLCN GAP activity toward RagC not directly measured in this study
   • Regulation of GAP membrane recruitment incompletely defined
4. 2015 High

   Discovery of recurrent somatic RRAGC mutations in follicular lymphoma that increase Raptor binding and confer amino-acid-independent mTORC1 activation established RagC as an oncoprotein and demonstrated that the RagC–Raptor interaction is the critical effector step in mammalian mTORC1 recruitment.

   Evidence Co-immunoprecipitation, amino acid deprivation assays, functional overexpression in HEK293T, extended targeted sequencing of follicular lymphoma cohorts

   PMID:26691987

   Open questions at the time

   • Crystal structure of mutant RagC–Raptor complex not determined
   • Downstream transcriptional consequences in lymphoma cells not fully mapped
5. 2016 High

   Showing that follicular lymphoma RRAGC mutations simultaneously increase Raptor binding and decrease FLCN interaction revealed a dual mechanism—gain of effector engagement plus loss of GAP regulation—explaining constitutive mTORC1 activation by these mutations.

   Evidence Co-IP in 293T and lymphoma cell lines, S6K phosphorylation western blots, yeast Gtr2 complementation

   PMID:27267853

   Open questions at the time

   • Quantitative GTP/GDP ratio of mutant RagC not directly measured
   • Therapeutic targeting of mutant RagC not tested
6. 2016 Medium

   Defining how Ragulator (Lam2) and SEAC/GATOR components tether and regulate the nucleotide state of the Gtr1–Gtr2 heterodimer at the vacuolar membrane clarified the scaffold requirements for RagC function and showed that loss of Gtr2 disinhibits TORC1.

   Evidence Co-IP of Lam2–Npr2–Gtr1, GTP/GDP-locked mutant rescue, Rps6 phosphorylation and vacuolar localization in fission yeast

   PMID:26609069 PMID:27227887

   Open questions at the time

   • Stoichiometry of the tethering complex not resolved
   • Mammalian Ragulator–RagC regulation not directly tested here
7. 2023 Medium

   Identification of de novo germline RRAGC missense variants causing a Mendelian developmental phenotype with constitutive mTORC1 overactivation demonstrated that dysregulation of the RagC switch has consequences beyond cancer, including increased cell size and disrupted TFEB-mediated lysosomal signaling.

   Evidence Patient-derived fibroblasts, HEK293 overexpression, mTOR pathway western blots, subcellular localization imaging, trio exome sequencing

   PMID:37057673

   Open questions at the time

   • Animal model of germline RRAGC mutations not reported
   • Full clinical spectrum not yet delineated
   • Mechanism distinguishing somatic oncogenic from germline developmental variants unclear

• The structural basis of how specific RRAGC mutations alter Raptor and FLCN binding surfaces, the in vivo consequences of germline RRAGC variants in animal models, and whether therapeutic mTORC1 inhibition can rescue RRAGC-driven diseases remain unresolved.
• No high-resolution structure of mammalian RagC–Raptor or RagC–FLCN complex with disease mutations
• No animal model of germline RRAGC variants reported
• Therapeutic efficacy of rapalogs or mTOR kinase inhibitors in RRAGC-mutant contexts not established