RRAGB

RRAGB (RagB) is a Ras-related GTPase that functions as part of a lysosomal Ragulator-RRAGA-RRAGB complex to control amino acid-dependent mTORC1 activation (PMID:36394332). Productive signaling requires RRAGB heterodimer formation, and TRIM37 promotes RRAGB activity by binding both MTOR and RRAGB, enhancing the MTOR-RRAGB interaction and driving lysosomal localization of MTOR; loss of this input reduces TFEB phosphorylation, allowing TFEB nuclear translocation and induction of autophagy/lysosome genes (PMID:29940807). Following lysosomal damage, RRAGB participates in the opposite direction, contributing to MTOR inactivation at the lysosome together with NUFIP2 and galectin-8 (LGALS8) (PMID:36394332). RRAGB is transcriptionally induced by HIF1A binding its promoter, establishing a HIF1A-RRAGB-mTORC1 positive feedback loop, and its heterodimer formation is blocked by the circular RNA circEXOC6B, which suppresses mTORC1 signaling and lowers HIF1A (PMID:35739524). In glioblastoma cells, RRAGB overexpression suppresses PI3K, phospho-AKT, mTOR and S6K and restrains proliferation, migration, invasion and cell cycle progression, acting upstream of AKT, since restoring AKT activation reverses these effects (PMID:37517217).

1. 2018 Medium

   Established how RRAGB-dependent mTORC1 activation is positively regulated, identifying TRIM37 as a factor that stabilizes the MTOR-RRAGB interaction and couples it to lysosomal recruitment and downstream TFEB control.

   Evidence Reciprocal Co-IP, lysosomal localization assays, TFEB phosphorylation and nuclear translocation readouts with knockdown/knockout

   PMID:29940807

   Open questions at the time

   • Does not resolve whether TRIM37 acts on RRAGB nucleotide state or GTPase cycle
   • Direct biochemical demonstration of the MTOR-RRAGB binding interface absent
   • RRAGB heterodimer partner (RagC/D) role not addressed here
2. 2022 Medium

   Showed that the Ragulator-RRAGA-RRAGB complex is also a node for shutting mTORC1 OFF, recruiting NUFIP2 and galectin-8 to inactivate MTOR after lysosomal membrane damage.

   Evidence Recruitment proteomics to damaged lysosomes, Co-IP, LysoIP, functional MTOR inactivation assays

   PMID:36394332

   Open questions at the time

   • RRAGB's specific contribution versus RRAGA not dissected
   • Mechanism by which damage signals reach the Rag complex unclear
   • No nucleotide-state analysis of RRAGB during inactivation
3. 2022 Medium

   Defined regulation of RRAGB at both the activity and transcriptional levels, with circEXOC6B blocking heterodimer assembly and HIF1A transcriptionally amplifying RRAGB in a feedback loop.

   Evidence RNA pull-down, mass spectrometry, RIP, Co-IP, ChIP, dual-luciferase assay, western blot

   PMID:35739524

   Open questions at the time

   • Identity of the obligate heterodimer partner not biochemically defined
   • Whether circEXOC6B competes at the GTPase or dimer interface unknown
   • Feedback loop characterized primarily in a single cancer context
4. 2023 Medium

   Tested RRAGB's net signaling output in glioblastoma, where gain-of-function suppressed PI3K/AKT/mTOR signaling and tumor phenotypes, placing RRAGB upstream of AKT via an epistasis rescue.

   Evidence Overexpression in GBM cell lines, pathway western blots, proliferation/migration/invasion assays, AKT rescue, xenograft and orthotopic models

   PMID:37517217

   Open questions at the time

   • Apparent contradiction with RRAGB as an mTORC1 activator not mechanistically reconciled
   • Direct molecular link from RRAGB to PI3K/AKT not identified
   • Single-lab, single-tumor-type finding
5. 2024 Low

   Extended RRAGB regulation to a miRNA axis in endothelial progenitor cells, where miR-21-3p targets RRAGB and RRAGB overexpression inhibits autophagy through mTOR.

   Evidence Luciferase reporter, overexpression, immunofluorescence/western for mTOR and autophagy markers, EPC functional assays

   PMID:39100534

   Open questions at the time

   • Limited mechanistic depth on RRAGB's direct action
   • Single lab, single study
   • Direct miR-21-3p/RRAGB binding effect on protein level not fully traced to phenotype
6. 2025 Low

   Linked RRAGB to disease pathophysiology in diabetic kidney disease via a circMRP4/miR-499-5p axis that upregulates RRAGB to activate mTORC1/P70S6K and drive podocyte apoptosis.

   Evidence Dual-luciferase, RIP, RNA pull-down, knockdown/overexpression, western blot for mTORC1/P70S6K

   PMID:39842531

   Open questions at the time

   • RRAGB role inferred through an indirect miRNA-sponge chain
   • Direct RRAGB mechanism not interrogated
   • Single lab, single study

• How RRAGB's nucleotide cycle and obligate heterodimer partner are biochemically controlled, and how it can both activate lysosomal mTORC1 and suppress PI3K/AKT in a context-dependent manner, remains unresolved.
• No structural or reconstituted GTPase-cycle analysis in the corpus
• Identity and regulation of the heterodimer partner undefined
• Mechanistic reconciliation of activating versus suppressive roles absent