Affinage

Showing RABGEF1 — RABEX5 is a alias.

RABGEF1

Rab5 GDP/GTP exchange factor · UniProt Q9UJ41

Length
491 aa
Mass
56.9 kDa
Annotated
2026-06-10
45 papers in source corpus 29 papers cited in narrative 29 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

RABGEF1 (Rabex-5) is a dual-function endosomal regulator that couples membrane trafficking to signal attenuation, acting both as a guanine-nucleotide exchange factor for Rab GTPases and as an A20-type zinc-finger E3 ubiquitin ligase (PMID:16462746, PMID:20655225). As a GEF, it catalyzes nucleotide exchange on Rab5 — at an intrinsically slow, rate-limiting rate (PMID:11419942) — and partners with Rabaptin-5 through its coiled-coil region to amplify this GEF activity and drive homotypic early-endosome fusion (PMID:16407276, PMID:11452015). Its recruitment to early endosomes is governed by a dedicated early endosomal targeting (EET) domain that is necessary and sufficient for membrane association and Rab5 activation (PMID:17699593), and is engaged by Rab22-GTP to establish a Rab22→Rabex-5→Rab5 activation relay (PMID:19759177); ubiquitin binding through its MIU and A20 zinc-finger domains, together with its own monoubiquitination, provides an additional GEF-independent route to endosomes and a cytosol-to-endosome cycle (PMID:16462746, PMID:18772883). In its second role, RABGEF1 functions as an E3 ligase that ubiquitinates Ras in a RIN1- and Ras-Tyr4-phosphorylation-dependent manner, driving Ras to endosomes and suppressing ERK signaling (PMID:20655225, PMID:32559233); this ligase activity, distinct from its GEF activity, restrains Ras-pathway output in vivo (PMID:20655224, PMID:15235600). Through these activities RABGEF1 negatively regulates receptor signaling across cell types: it limits FcεRI- and c-Kit-driven mast cell activation and promotes receptor internalization (PMID:15235600, PMID:17341663, PMID:16533754), and in epithelia it acts upstream of IL-1R/MYD88/NF-κB and p38 signaling to maintain skin and intestinal homeostasis (PMID:27820702, PMID:31628426). In neurons it additionally serves as a GEF for Rab17 to support dendrite morphogenesis (PMID:23430262).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 High

    Establishing that Rabex-5 is an intrinsically slow GEF for Rab5 defined nucleotide exchange as the rate-limiting control point of the Rab cycle, framing why accessory regulation is needed.

    Evidence Quantitative in vitro kinetic analysis with fluorescent nucleotide analogs on Vps9p/Rabex-5 and cognate GTPases

    PMID:11419942

    Open questions at the time
    • Did not address how partners or membrane context accelerate exchange in vivo
    • Kinetics measured in isolation, not in a reconstituted endosomal context
  2. 2001 High

    Identifying Rabaptin-5 as a Rabex-5 partner that boosts its GEF activity explained how a weak exchange factor achieves productive Rab5 activation and endosome fusion.

    Evidence Reconstitution with recombinant proteins, in vitro GEF and endosome fusion assays

    PMID:11452015

    Open questions at the time
    • Structural basis of GEF stimulation not resolved
    • Mechanism of Rab5-dependent membrane recruitment of the complex left open
  3. 2003 High

    Linking the Rabaptin-5–Rabex-5 complex to GGA adaptors connected the GEF machinery to clathrin-dependent cargo sorting at early endosomes.

    Evidence Reciprocal co-IP and pull-down mapping with mutagenesis plus localization microscopy

    PMID:12505986

    Open questions at the time
    • Functional consequence for specific cargo trafficking not fully defined
    • Whether GGA interaction modulates Rabex-5 GEF or E3 activity unknown
  4. 2004 High

    Demonstrating that RabGEF1 binds Ras and limits FcεRI-driven mast cell activation revealed an unexpected signal-attenuation role beyond membrane traffic.

    Evidence Co-IP plus knockout mouse mast cells with degranulation, lipid mediator, and cytokine readouts

    PMID:15235600

    Open questions at the time
    • Molecular mechanism of Ras inhibition not yet defined
    • Which RabGEF1 domain mediated the effect unresolved at this stage
  5. 2006 High

    Structural and biochemical work defined two ubiquitin-binding modules (MIU and A20 zinc finger) and assigned intrinsic E3 ligase activity to the zinc finger, establishing Rabex-5 as a ubiquitin-handling enzyme.

    Evidence 2.5-Å crystal structure with mutagenesis, ubiquitin-binding and in vitro E3 ligase assays; corroborating deletion-mapping and Rabaptin-5 interaction study

    PMID:16407276 PMID:16462746

    Open questions at the time
    • Physiological substrates of the E3 activity not identified here
    • How ubiquitin binding and E3 activity are coordinated in cells unaddressed
  6. 2009 High

    Mapping the EET domain and identifying Rab22-GTP as its ligand explained how Rabex-5 is recruited to endosomes independently of Rabaptin-5, defining a Rab22→Rabex-5→Rab5 relay.

    Evidence EET deletion constructs with in vivo Rab5 activation assays; Rab22 pull-down, shRNA knockdown, and endosome enlargement synergy

    PMID:17699593 PMID:19759177

    Open questions at the time
    • How the Rab22 and Rabaptin-5 recruitment routes are integrated unclear
    • Upstream control of Rab22 activation not addressed
  7. 2008 High

    Showing that ubiquitin binding and monoubiquitination govern Rabex-5's cytosol-to-endosome cycle established self-regulation independent of its GEF activity.

    Evidence Domain mutant analysis, subcellular fractionation, microscopy, and co-IP

    PMID:18772883

    Open questions at the time
    • Ligase responsible for Rabex-5 monoubiquitination not identified
    • Trigger for the cycle in response to signaling unknown
  8. 2010 High

    Demonstrating RIN1-dependent Ras ubiquitination by Rabex-5 in mammalian cells and Drosophila established the E3 (not GEF) activity as the effector that endosomally sequesters Ras and dampens ERK signaling.

    Evidence Biochemical ubiquitination assays, RIN1 siRNA epistasis, ERK readouts; parallel Drosophila domain-specific genetics and epistasis; KO/rescue mast cell signaling and c-Kit internalization studies

    PMID:16533754 PMID:20655224 PMID:20655225

    Open questions at the time
    • Type and topology of the ubiquitin modification on Ras not defined
    • Whether ubiquitinated Ras is degraded or only relocalized unresolved
  9. 2007 High

    Domain-specific rescue in RabGEF1-deficient mast cells separated the functions: the Vps9 GEF domain normalizes activation phenotypes, the zinc finger provides E3 activity, and the coiled-coil binds Rabaptin-5 to maintain surface receptor levels.

    Evidence Lentiviral domain-deletion mutant rescue in KO mast cells with internalization, degranulation, and cytokine readouts

    PMID:17341663

    Open questions at the time
    • How the separate domains are coordinated within one signaling event unclear
    • Direct substrates in mast cells not enumerated
  10. 2013 High

    Identifying Rabex-5 as a GEF for Rab17 in neurons broadened its GEF substrate range and linked it to dendrite morphogenesis distinct from its Rab5 role.

    Evidence Yeast two-hybrid with GDP-locked Rab17, neuronal translocation assays, and shRNA knockdown with morphometry

    PMID:23430262

    Open questions at the time
    • Biochemical exchange kinetics on Rab17 not measured
    • Selectivity between Rab5 and Rab17 in neurons not dissected
  11. 2012 Medium

    Connecting Rabex-5's MIU to ubiquitinated L1 cargo, and showing GEF activity acts as an intramolecular switch over cargo binding, linked its trafficking and ubiquitin-recognition functions mechanistically.

    Evidence Co-IP, domain mutants, siRNA knockdown, internalization assays, and hinge-flexibility analysis

    PMID:22846990 PMID:23048039

    Open questions at the time
    • Single-lab findings without independent replication
    • Structural basis of the HB-VPS9 hinge switch not resolved at high resolution
  12. 2015 Medium

    Competing models of Rab5 activation were tested: kinetic/modeling and domain studies argued either positive feedback or a feed-forward mechanism requiring Rab4 and ubiquitylated cargo for Rabaptin-5 recruitment.

    Evidence Mathematical modeling with cellular kinetic measurements; Rabaptin-5 domain deletion and Rab4/Rab5 RNAi epistasis with endosome morphology

    PMID:20169068 PMID:26430212

    Open questions at the time
    • The two models are not reconciled into a single quantitative framework
    • Single-lab studies with no independent replication of the feed-forward claim
  13. 2016 High

    Conditional epithelial knockouts placed RABGEF1 upstream of IL-1R/MYD88/NF-κB signaling, defining a tissue-homeostatic function in skin barrier maintenance.

    Evidence Keratinocyte-specific KO with MYD88 and IL1R1 double-KO epistasis and barrier/NF-κB readouts; parallel D2LR–Rabex-5 and Cereblon–Rabex-5 interaction studies

    PMID:27601648 PMID:27820702 PMID:27922607

    Open questions at the time
    • Direct molecular substrate linking RABGEF1 loss to IL-1R/MYD88 hyperactivation not identified
    • Whether GEF or E3 activity mediates the epithelial phenotype not resolved
  14. 2019 High

    Intestinal epithelial deletion showed RABGEF1 controls early endocytosis and restrains microbiota- and MYD88-dependent p38 signaling, extending its homeostatic role to gut epithelium.

    Evidence IEC-specific conditional KO, in vitro endocytosis assays, p38 inhibition, MYD88 epistasis, and germ-free/antibiotic experiments

    PMID:31628426

    Open questions at the time
    • Mechanistic link between endocytic defect and p38 activation not detailed
    • Cargo whose mistrafficking drives inflammation unknown
  15. 2020 High

    Identifying Ras Tyr4 phosphorylation (by JAK2/SRC) as a prerequisite for Rabex-5-mediated ubiquitination revealed a kinase-gated switch coupling Ras activation to its own ubiquitin-mediated attenuation.

    Evidence In vitro ubiquitination and kinase assays plus Drosophila phosphomimic/phospho-dead genetic rescue

    PMID:32559233

    Open questions at the time
    • Which kinase phosphorylates Ras-Y4 physiologically in mammals not established
    • Quantitative contribution of this switch to oncogenic Ras control unmeasured
  16. 2024 Medium

    New genetic and biochemical contexts expanded RABGEF1's reach into Notch/PI3K restriction, TNF-induced necroptosis, and competition between Rab GTPases for activation.

    Evidence Drosophila domain-specific genetics for Notch/PTEN/PI3K; co-IP and gain/loss-of-function for cIAP1/RIPK1 necrosome; dominant-negative Rab5/Rab21 competition microscopy; photoreceptor KO autophagy phenotype

    PMID:33362196 PMID:38377943 PMID:39466792 PMID:40519268

    Open questions at the time
    • Several contexts rest on single-lab studies without replication
    • Direct substrate/binding measurements (e.g., Rab21 affinity) are indirect

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RABGEF1 selects between its GEF and E3 activities, and which substrate spectrum it engages in each tissue, remains unresolved.
  • No unified model integrating GEF, E3, and ubiquitin-recognition functions across cell types
  • Full physiological substrate repertoire of the E3 activity beyond Ras unknown
  • Structural basis for switching between activities not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4 GO:0016874 ligase activity 3 GO:0060089 molecular transducer activity 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005768 endosome 4 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 1
Partners
BIRC2CRBNHRASRAB17RAB22ARAB5RABEP1RIN1
Complex memberships
Rabex-5–Rabaptin-5 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Crystal structure of Rabex-5 N-terminal region bound to ubiquitin at 2.5-Å resolution revealed two ubiquitin-binding sites: an inverted ubiquitin-interacting motif (MIU) that binds the canonical Ile44 hydrophobic patch on ubiquitin (~29 µM), and a diaromatic patch on the A20 zinc finger that binds a polar region centered on Asp58 of ubiquitin (~22 µM). The A20 zinc-finger diaromatic patch mediates ubiquitin-ligase (E3) activity by directly recruiting a ubiquitin-loaded ubiquitin-conjugating enzyme. X-ray crystallography (2.5 Å), mutagenesis, in vitro ubiquitin-binding and E3 ligase assays Nature structural & molecular biology High 16462746
2006 Rabex-5 residues 401–462 (coiled-coil) interact with residues 551–661 of Rabaptin-5. Rabex-5 undergoes ubiquitination and binds ubiquitin via its N-terminal A20-like zinc finger (residues 1–76) and adjacent α-helix, not via a C-terminal CUE-like domain. The zinc finger displays intrinsic E3 ubiquitin ligase activity in vitro. Deletion mapping, co-immunoprecipitation, in vitro ubiquitination assay, ubiquitin-binding assay The Journal of biological chemistry High 16407276
2001 Rabaptin-5 increases the nucleotide exchange (GEF) activity of Rabex-5 on Rab5 when physically associated. Rab5-dependent recruitment of Rabaptin-5 to early endosomes requires its physical association with Rabex-5. Complex formation between Rabaptin-5 and Rabex-5 is essential for early endosome homotypic fusion. Reconstitution with recombinant proteins, in vitro GEF activity assay, endosome fusion assay Molecular biology of the cell High 11452015
2001 Vps9p and Rabex-5 are weak GDP/GTP exchange factors for their cognate GTPases (Ypt51p/Rab5), with a maximal rate constant for GDP release of ~0.01 s⁻¹, orders of magnitude lower than other exchange factors, suggesting rate-limiting control at the nucleotide exchange step of the Rab cycle. Quantitative kinetic analysis of GEF activity using fluorescent nucleotide analogs in vitro Journal of molecular biology High 11419942
2003 GGA proteins interact with the Rabaptin-5–Rabex-5 complex in a bipartite manner: GGA-GAE domains bind an FGPLV sequence (residues 439–443) in Rabaptin-5, and GGA-GAT domains bind the C-terminal coiled-coils of Rabaptin-5. GGA–Rabaptin-5 interaction decreases clathrin binding to the GGA-hinge domain, and GFP-Rabaptin-5 expression shifts endogenous GGA1 and associated cargo to enlarged early endosomes. Co-immunoprecipitation, pull-down assays, mutagenesis, subcellular localization by fluorescence microscopy The EMBO journal High 12505986
2008 Ubiquitin binding via the MIU and A20 zinc-finger domains is essential for recruitment of Rabex-5 from the cytosol to early endosomes, independently of its GEF activity and of Rab5. Monoubiquitinated Rabex-5 is enriched in the cytosol, consistent with a cycle of ubiquitin binding and monoubiquitination regulating Rabex-5 endosomal association. Domain mutant analysis, subcellular fractionation, fluorescence microscopy, co-immunoprecipitation The EMBO journal High 18772883
2009 Rab22-GTP (but not Rab22-GDP) directly binds the early endosomal targeting (EET) domain (residues 81–230) of Rabex-5, recruiting it to early endosomes to activate Rab5, establishing a Rab22→Rabex-5→Rab5 signaling relay. Rab22 knockdown abolishes Rabex-5 membrane targeting, and Rab22/Rab5 co-expression causes synergistic endosome enlargement dependent on Rabex-5. Pull-down assay, shRNA knockdown, fluorescence microscopy, endosome enlargement assay Molecular biology of the cell High 19759177
2007 Rabex-5 possesses an early endosomal targeting (EET) domain (residues 81–230) comprising a membrane-binding motif (81–135) and a helical bundle domain (135–230) that is necessary and sufficient for early endosomal association and Rab5 activation in vivo, independently of the Rabaptin-5-binding C-terminal domain. Deletion constructs, fluorescence microscopy, in vivo Rab5 activation assay (endosome enlargement) Molecular biology of the cell High 17699593
2010 Rabex-5 functions as an E3 ubiquitin ligase for Ras, promoting Ras ubiquitination and endosomal localization of Ras, and suppressing ERK activation. The Ras effector RIN1 is required for Rabex-5-dependent Ras ubiquitination, suggesting RIN1 couples Ras activation to ubiquitin-mediated feedback attenuation. Biochemical ubiquitination assay, co-immunoprecipitation, RIN1 siRNA knockdown, ERK activation assay Current biology : CB High 20655225
2010 In Drosophila, Rabex-5 ubiquitin ligase (E3) activity—not its Rab5 GEF activity—is required to restrict Ras signaling in wing vein patterning and eye fate determination. Genetic interaction experiments place Rabex-5 at the step of Ras, and tissue culture assays show that Rabex-5 promotes Ras ubiquitination. Drosophila genetics (overexpression, domain-specific mutant transgenes), genetic epistasis, tissue culture Ras ubiquitination assay Current biology : CB High 20655224
2004 RabGEF1 binds to Ras and negatively regulates Ras activation and downstream effector pathways (including ERK) in FcεRI-dependent mast cell activation; RabGEF1-deficient mast cells exhibit enhanced degranulation, lipid mediator release, and cytokine production. Co-immunoprecipitation (Ras binding), knockout mouse mast cells, functional mast cell activation assays (degranulation, cytokine ELISA) Nature immunology High 15235600
2007 RabGEF1's Vps9 (GEF) domain is required to normalize FcεRI-mediated mast cell functional activation phenotypes in RabGEF1-deficient cells, while its zinc finger (E3) domain is required for ubiquitin ligase activity and the coiled-coil domain is required for Rabaptin-5 binding and maintenance of surface FcεRI levels. Lentiviral domain-deletion mutant rescue in KO mast cells, FcεRI internalization assay, degranulation assay, cytokine production assay Blood High 17341663
2006 RabGEF1-deficient mast cells exhibit enhanced and prolonged Ras and ERK activation, elevated IL-6 secretion, increased JNK activation, and elevated Akt activation after SCF stimulation. c-Kit internalization is delayed in the absence of RabGEF1, and wild-type RabGEF1 re-expression normalizes c-Kit internalization, demonstrating a positive role for RabGEF1 in receptor endocytosis. KO bone-marrow mast cells, lentiviral rescue, phospho-kinase Western blotting, c-Kit internalization assay (flow cytometry) Proceedings of the National Academy of Sciences of the United States of America High 16533754
2013 Rabex-5 acts as a GEF for Rab17 in hippocampal neurons (identified by yeast two-hybrid with GDP-locked Rab17 and confirmed by translocation assays). Rabex-5 expression promotes translocation of Rab17 from the cell body to dendrites. shRNA knockdown of Rabex-5 or Rab5 inhibits both axon and dendrite morphogenesis, while Rab17 knockdown affects dendrite morphogenesis alone. Yeast two-hybrid, Rab17 translocation assay in neurons, shRNA knockdown, morphometric analysis The Journal of biological chemistry High 23430262
2012 Rabex-5 associates with ubiquitinated L1 cell adhesion molecule via its MIU domain (not the A20 zinc finger), dependent on ubiquitin on Rab5 lysine residues of L1. Rabex-5 expression accelerates internalization of ubiquitinated L1, while Rabex-5 knockdown impairs internalization of ubiquitinated L1 but not an ubiquitination-deficient mutant, directing ubiquitinated L1 toward lysosomal degradation. Co-immunoprecipitation, domain mutant analysis, siRNA knockdown, internalization/trafficking assay, live fluorescence microscopy The Journal of biological chemistry Medium 22846990
2012 Rabex-5 GEF activity acts as an intramolecular switch controlling the MIU domain's interaction with ubiquitinated cargo: GEF-impaired mutants increase flexibility of the HB-VPS9 hinge region and alter ubiquitinated L1 binding. Coupled monoubiquitination status of Rabex-5 is associated with its interaction with ubiquitinated L1, regulating spatiotemporal cargo exchange. GEF domain mutants, co-immunoprecipitation, structural analysis of hinge flexibility, ubiquitination assays The Journal of biological chemistry Medium 23048039
2015 Rabaptin-5 membrane recruitment requires binding to both Rab4 and Rabex-5 (which recognizes ubiquitylated cargo), but not Rab5. Deletion of either Rab5-binding domain in Rabaptin-5 or silencing Rab5 did not prevent Rabaptin-5 recruitment but produced giant endosomes with early and late endosomal characteristics, indicating a feed-forward (not positive feedback) model of Rab5 activation. Deletion analysis of Rabaptin-5 domains, siRNA knockdown of Rab5/Rab4, fluorescence microscopy, endosome morphology assay Journal of cell science Medium 26430212
2016 D2 dopamine receptor long isoform (D2LR) directly binds and activates Rabex-5, promoting early endosome formation. Endosomes containing D2LR and PDGFRβ are transported to the Golgi where they trigger Gαi3-mediated ERK signaling, regulating dendritic spine density and neuronal activity in striatopallidal medium spiny neurons. Co-immunoprecipitation (D2LR–Rabex-5 binding), endosome/Golgi fractionation, KO mouse analysis, dendritic spine morphometry Molecular psychiatry Medium 27922607
2010 Mathematical modeling and kinetic analysis demonstrate that the Rabex-5/Rabaptin-5 complex constitutes a positive feedback loop for Rab5 activation on endosomal membranes, with a threshold ('delayed response') requiring above-endogenous Rab5 or Rabex-5 concentrations. A direct Rabaptin-5-independent (EET domain-mediated) Rabex-5 pathway reduces this threshold by elevating basal Rab5-GTP. Mathematical modeling, quantitative kinetic analysis of Rab5 activation in cells, fluorescence microscopy PloS one Medium 20169068
2001 GST-Rab33b (GTP-locked) pulls down Rabaptin-5 and Rabex-5 from cell lysates, suggesting Rab33b can interact with the Rabaptin-5–Rabex-5 complex in a GTP-dependent manner, potentially linking Golgi Rab33b to endocytic machinery. GST pull-down, Western blot, mass spectrometry identification FEBS letters Low 11718716
2016 Rabex-5 forms a complex with Cereblon (the IMiD receptor). Lenalidomide treatment prevents Cereblon–Rabex-5 association; a mutation in the IMiD-binding site of Cereblon increases their co-immunoprecipitation. Rabex-5 knockdown upregulates TLR-induced cytokine and type 1 IFN production via a STAT1/IRF activating pathway, defining Rabex-5 as a negative regulator of TLR-induced innate immune responses. Co-immunoprecipitation, siRNA knockdown in THP-1 cells, cytokine/IFN production assay Proceedings of the National Academy of Sciences of the United States of America Medium 27601648
2016 Keratinocyte-specific deletion of RABGEF1 causes aberrant activation of the intrinsic IL-1R/MYD88/NF-κB signaling pathway and MYD88-dependent abnormalities in skin barrier structural proteins. Ablation of MYD88 or deletion of IL-1R1 in RABGEF1-deficient keratinocytes restores skin homeostasis, placing RABGEF1 upstream of IL-1R/MYD88 signaling in keratinocytes. Conditional KO (keratinocyte-specific), epistasis (MYD88 and IL1R1 double KO), skin barrier function assays, NF-κB signaling assays The Journal of clinical investigation High 27820702
2019 IEC-specific RABGEF1 deletion impairs early endocytic events in intestinal epithelial cells, increases p38 MAPK-dependent signaling, and enhances chemokine secretion in vitro. Spontaneous colitis in Rabgef1IEC-KO mice is dependent on microbiota-derived signals and intrinsic MYD88-dependent pathways in vivo, placing RABGEF1 upstream of MYD88 signaling in intestinal epithelia. IEC-specific conditional KO, in vitro endocytosis assay, p38 inhibition, MYD88 epistasis, germ-free/antibiotic experiments Mucosal immunology High 31628426
2015 RabGEF1 binds Rac1; RabGEF1 knockdown in NGF-differentiated PC12 cells enhances Rac1 activation upon NGF treatment, identifying RabGEF1 as a negative regulator of NGF-induced Rac1 activation. RabGEF1 also co-immunoprecipitates with NMDA receptor subunit NR2B and its binding partner SynGAP, and negatively regulates nitric oxide synthase activity induced by NMDA receptor stimulation. Co-immunoprecipitation (Rac1, NR2B, SynGAP), antisense stable knockdown in PC12 cells, Rac1 activation assay (pull-down), NOS activity assay PloS one Medium 26588713
2020 Rabex-5-mediated Ras ubiquitination requires Ras Tyrosine 4 (Y4). Y4 substitution mutants insensitive to phosphorylation are not ubiquitinated by Rabex-5 and show Ras gain-of-function phenotypes in vivo. A Y4 phosphomimic increases Rabex-5-mediated ubiquitination and blocks oncogenic Ras phenotypes in a Rabex-5-dependent manner. In vitro, JAK2 and SRC can phosphorylate Ras at Y4. In vitro ubiquitination assay, Drosophila genetics (mutant transgenes), phospho-specific antibody, in vitro kinase assay with JAK2/SRC/EGFR PLoS genetics High 32559233
2024 Rabex-5 E3 domain is required to inhibit Notch signaling in Drosophila wing epithelium. Paradoxically, Rabex-5 with an impaired E3 domain but active Rab5 GEF domain suppresses Notch loss-of-function phenotypes and enhances Notch gain-of-function phenotypes, consistent with the GEF domain positively regulating Notch. Rabex-5 E3 activity also inhibits overgrowth caused by loss of PTEN or activation of PI3K (but not activation of AKT). Drosophila genetics (domain-specific mutant transgenes), genetic interaction analysis, wing phenotype scoring PloS one Medium 39466792
2024 RABGEF1 interacts with cIAP1, inhibiting its function and facilitating RIPK1 phosphorylation and necrosome formation to promote TNF-induced necroptosis. Both E3 ubiquitin ligase and GEF activities of RABGEF1 contribute to the pro-necrotic effect; the Smac mimetic SM-164 abolishes RABGEF1-dependent necroptosis promotion. Co-immunoprecipitation (RABGEF1–cIAP1), overexpression and siRNA knockdown, RIPK1 phosphorylation assay, necrosome formation assay in L929 cells Biochemical and biophysical research communications Medium 38377943
2020 In photoreceptors, RabGEF1 interacts with Rabaptin-5, and RabGEF1 loss leads to reduction of early endosomes. Rabgef1-/- photoreceptors accumulate macromolecular aggregates in autophagosome-like vacuoles and show enhanced LC3A/B and p62 immunostaining, consistent with compromised autophagy downstream of endocytic dysfunction. Co-immunoprecipitation (RabGEF1–Rabaptin-5), KO mouse photoreceptors, subcellular fractionation, electron microscopy, immunostaining (LC3, p62) PLoS genetics Medium 33362196
2025 Rab21 and Rab5 compete for activation by Rabex-5, with evidence suggesting Rab21 may have higher affinity for Rabex-5 than Rab5 in vivo. Modulation of Rab5 or Rab21 dominant-negative binding to Rabex-5 supports this competitive model. Dominant-negative mutant analysis, fluorescence microscopy, endosome size measurement, co-localization Frontiers in cell and developmental biology Low 40519268

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Structural basis for ubiquitin recognition and autoubiquitination by Rabex-5. Nature structural & molecular biology 177 16462746
2001 Functional synergy between Rab5 effector Rabaptin-5 and exchange factor Rabex-5 when physically associated in a complex. Molecular biology of the cell 172 11452015
2003 Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5 complex. The EMBO journal 131 12505986
2006 The Rab5 guanine nucleotide exchange factor Rabex-5 binds ubiquitin (Ub) and functions as a Ub ligase through an atypical Ub-interacting motif and a zinc finger domain. The Journal of biological chemistry 105 16407276
2001 Identification of rabaptin-5, rabex-5, and GM130 as putative effectors of rab33b, a regulator of retrograde traffic between the Golgi apparatus and ER. FEBS letters 102 11718716
2010 Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Current biology : CB 87 20655225
2008 Ubiquitin binding and conjugation regulate the recruitment of Rabex-5 to early endosomes. The EMBO journal 71 18772883
2009 Rabex-5 is a Rab22 effector and mediates a Rab22-Rab5 signaling cascade in endocytosis. Molecular biology of the cell 63 19759177
2001 Vps9, Rabex-5 and DSS4: proteins with weak but distinct nucleotide-exchange activities for Rab proteins. Journal of molecular biology 62 11419942
2010 Rabex-5 ubiquitin ligase activity restricts Ras signaling to establish pathway homeostasis in Drosophila. Current biology : CB 57 20655224
2004 RabGEF1 is a negative regulator of mast cell activation and skin inflammation. Nature immunology 54 15235600
2013 Rabex-5 protein regulates dendritic localization of small GTPase Rab17 and neurite morphogenesis in hippocampal neurons. The Journal of biological chemistry 42 23430262
2007 Rabaptin-5-independent membrane targeting and Rab5 activation by Rabex-5 in the cell. Molecular biology of the cell 42 17699593
2015 Rabaptin5 is recruited to endosomes by Rab4 and Rabex5 to regulate endosome maturation. Journal of cell science 31 26430212
2007 Roles of RabGEF1/Rabex-5 domains in regulating Fc epsilon RI surface expression and Fc epsilon RI-dependent responses in mast cells. Blood 28 17341663
2016 Endocytosis following dopamine D2 receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFRβ signaling in striatopallidal medium spiny neurons. Molecular psychiatry 27 27922607
2006 RabGEF1 regulates stem cell factor/c-Kit-mediated signaling events and biological responses in mast cells. Proceedings of the National Academy of Sciences of the United States of America 27 16533754
2010 Delayed onset of positive feedback activation of Rab5 by Rabex-5 and Rabaptin-5 in endocytosis. PloS one 21 20169068
2014 Expression of RABEX-5 and its clinical significance in prostate cancer. Journal of experimental & clinical cancer research : CR 19 24716822
2013 RABEX-5 plays an oncogenic role in breast cancer by activating MMP-9 pathway. Journal of experimental & clinical cancer research : CR 18 23941575
2013 Rabaptin-5 and Rabex-5 are neoplastic tumour suppressor genes that interact to modulate Rab5 dynamics in Drosophila melanogaster. Developmental biology 18 24104056
2016 Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production. Proceedings of the National Academy of Sciences of the United States of America 15 27601648
2014 RABEX-5 is upregulated and plays an oncogenic role in gastric cancer development by activating the VEGF signaling pathway. PloS one 14 25427001
2020 A conserved, N-terminal tyrosine signal directs Ras for inhibition by Rabex-5. PLoS genetics 12 32559233
2016 Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis. The Journal of clinical investigation 12 27820702
2012 Rabex-5 protein regulates the endocytic trafficking pathway of ubiquitinated neural cell adhesion molecule L1. The Journal of biological chemistry 12 22846990
2020 Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration. PLoS genetics 11 33362196
2010 Signal transduction: RABGEF1 fingers RAS for ubiquitination. Current biology : CB 10 20692608
2015 Drosophila Rabex-5 restricts Notch activity in hematopoietic cells and maintains hematopoietic homeostasis. Journal of cell science 8 26567216
2015 RabGEF1/Rabex-5 Regulates TrkA-Mediated Neurite Outgrowth and NMDA-Induced Signaling Activation in NGF-Differentiated PC12 Cells. PloS one 8 26588713
2012 Spatiotemporal regulation of the ubiquitinated cargo-binding activity of Rabex-5 in the endocytic pathway. The Journal of biological chemistry 8 23048039
2019 Epithelial RABGEF1 deficiency promotes intestinal inflammation by dysregulating intrinsic MYD88-dependent innate signaling. Mucosal immunology 7 31628426
2016 RABEX-5 overexpression in gastric cancer is correlated with elevated MMP-9 level. American journal of translational research 7 27347344
2013 Rabex-5 determines the neurite localization of its downstream Rab proteins in hippocampal neurons. Communicative & integrative biology 6 24265856
2017 Higher RABEX-5 mRNA predicts unfavourable survival in patients with colorectal cancer. European review for medical and pharmacological sciences 5 28617553
2010 Thymic stromal lymphopoietin contributes to myeloid hyperplasia and increased immunoglobulins, but not epidermal hyperplasia, in RabGEF1-deficient mice. The American journal of pathology 5 20829437
2024 Rabex-5 E3 and Rab5 GEF domains differ in their regulation of Ras, Notch, and PI3K signaling in Drosophila wing development. PloS one 3 39466792
2011 [The expression and clinical significance of RABEX-5 and RAB5 in breast cancer]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 2 21500550
2005 RabGEF1, a negative regulator of Ras signalling, mast cell activation and skin inflammation. Novartis Foundation symposium 2 16605131
2025 Rab21 recruits EEA1 and competes with Rab5 for Rabex-5 activation. Frontiers in cell and developmental biology 1 40519268
2024 Guanine nucleotide exchange factor RABGEF1 facilitates TNF-induced necroptosis by targeting cIAP1. Biochemical and biophysical research communications 1 38377943
2020 RabGEF1 functions as an oncogene in U251 glioblastoma cells and is involved in regulating AKT and Erk pathways. Experimental and molecular pathology 1 33166495
2015 Assay of Rab17 and its guanine nucleotide exchange factor Rabex-5 in the dendrites of hippocampal neurons. Methods in molecular biology (Clifton, N.J.) 1 25800847
2013 Role of Rabex-5 in the sorting of ubiquitinated cargo at an early stage in the endocytic pathway. Communicative & integrative biology 1 23986801
2013 [The effect of RABEX-5 downregulation on the chemosensitivity of human breast cancer cells]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 0 24490494

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