Affinage

RABGEF1

Rab5 GDP/GTP exchange factor · UniProt Q9UJ41

Length
491 aa
Mass
56.9 kDa
Annotated
2026-04-28
45 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RABGEF1 (Rabex-5) is a bifunctional regulator of endosomal trafficking and Ras/innate immune signaling that couples guanine-nucleotide exchange factor (GEF) activity with E3 ubiquitin ligase activity. Its Vps9 domain catalyzes GDP/GTP exchange on Rab5 (and Rab17/Rab21), and together with Rabaptin-5 drives early endosome fusion and receptor endocytosis; membrane recruitment requires an early endosomal targeting domain that integrates ubiquitin binding (via A20 zinc finger and MIU motifs) and Rab22-GTP interaction (PMID:11452015, PMID:16462746, PMID:17699593, PMID:19759177). The N-terminal A20-type zinc finger functions as an E3 ubiquitin ligase that mono- and di-ubiquitinates Ras in a Tyr4-phosphorylation-dependent manner, driving Ras endosomal sequestration and attenuating ERK signaling both in mammalian cells and in Drosophila (PMID:20655225, PMID:20655224, PMID:32559233). In epithelial cells and mast cells, RABGEF1 loss derepresses MYD88/NF-κB and Ras/ERK signaling, producing spontaneous inflammation, enhanced mast cell degranulation, and impaired receptor internalization, establishing RABGEF1 as a negative regulator of innate immune activation and receptor tyrosine kinase signaling (PMID:15235600, PMID:27820702, PMID:31628426).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Establishing that Rabex-5 is a Rab5 GEF whose exchange activity is stimulated by Rabaptin-5 and that the complex is essential for early endosome fusion answered the fundamental question of how Rab5 is activated on endosomes.

    Evidence Reconstituted GEF assay and endosome fusion assay with recombinant proteins, plus quantitative kinetic analysis of exchange rate

    PMID:11419942 PMID:11452015

    Open questions at the time
    • Mechanism of autoinhibition relief by Rabaptin-5 not defined structurally
    • In vivo relevance not yet tested at this stage
  2. 2003 High

    Linking the Rabaptin-5–Rabex-5 complex to GGA clathrin adaptors revealed how the endosomal GEF machinery intersects with clathrin-dependent sorting.

    Evidence Co-immunoprecipitation, GST pulldown with domain mapping, GFP-Rabaptin-5 overexpression relocalization of GGA1 and cargo

    PMID:12505986

    Open questions at the time
    • Functional consequence of GGA–Rabex-5 coupling on cargo fate not directly tested
    • Whether Rabex-5 GEF activity is regulated by GGA binding is unknown
  3. 2004 High

    Demonstrating that RabGEF1 binds Ras and that its loss hyperactivates mast cells established a signaling-regulatory role beyond vesicle trafficking.

    Evidence Co-IP of RabGEF1–Ras, RabGEF1-knockout mice with skin inflammation and hyperactive mast cell degranulation/cytokine secretion

    PMID:15235600

    Open questions at the time
    • Molecular mechanism of Ras regulation (ubiquitination vs. sequestration) not yet identified
    • Contribution of GEF versus E3 activity to mast cell phenotype unresolved
  4. 2006 High

    Structural and biochemical characterization of the A20 zinc finger as a dual ubiquitin-binding/E3 ligase module, and the MIU as a second ubiquitin-binding site, defined the molecular basis for Rabex-5's ubiquitin-dependent functions.

    Evidence 2.5 Å crystal structure of N-terminal region bound to ubiquitin, in vitro E3 ligase assays, mutagenesis of both binding sites

    PMID:16407276 PMID:16462746

    Open questions at the time
    • Physiological substrate of E3 activity not yet identified at this point
    • How the two ubiquitin-binding modes cooperate in vivo remained unclear
  5. 2006 High

    Showing that RabGEF1-deficient mast cells display prolonged Ras/ERK/JNK/Akt activation and delayed c-Kit internalization after SCF stimulation established RabGEF1 as a negative feedback regulator of receptor tyrosine kinase signaling.

    Evidence Knockout mast cells with pERK/pJNK/pAkt immunoblots, c-Kit internalization by flow cytometry, lentiviral rescue

    PMID:16533754

    Open questions at the time
    • Whether delayed c-Kit internalization is cause or consequence of enhanced signaling not resolved
    • Relative contribution of GEF vs. E3 activity not separated
  6. 2007 High

    Identification of the early endosomal targeting (EET) domain (aa 81–230) as necessary and sufficient for membrane recruitment and Rab5 activation resolved how Rabex-5 reaches endosomes independently of Rabaptin-5.

    Evidence Systematic deletion mutagenesis with fluorescence microscopy and in vivo Rab5 activation assays

    PMID:17341663 PMID:17699593

    Open questions at the time
    • Receptor or lipid determinant on the membrane recognized by the EET domain not identified
    • Domain rescue in mast cells showed GEF domain corrects degranulation but did not test EET role in mast cell context
  7. 2008 High

    Demonstrating that ubiquitin binding via MIU/A20 domains is essential for cytosol-to-endosome recruitment established a ubiquitin-dependent membrane targeting mechanism for Rabex-5.

    Evidence Subcellular fractionation of ubiquitin-binding mutants, live-cell imaging showing cytosolic retention of mutants

    PMID:18772883

    Open questions at the time
    • Identity of the endosomal ubiquitinated partner(s) that recruit Rabex-5 not determined
    • Relative contributions of ubiquitin binding vs. Rab22 binding for endosomal targeting not quantified
  8. 2009 High

    Identifying Rab22-GTP as a direct recruiter of Rabex-5 via the EET domain established a Rab22→Rabex-5→Rab5 signaling cascade for endosome maturation.

    Evidence GST pulldown with GTPγS-loaded Rab22, Rab22 shRNA knockdown abolishing Rabex-5 membrane targeting, EGF degradation assays

    PMID:19759177

    Open questions at the time
    • Whether Rab22 and ubiquitin cooperate or act redundantly for Rabex-5 recruitment is unclear
    • No structural basis for the Rab22–EET interaction
  9. 2010 High

    Identifying Ras as the physiological substrate of Rabex-5 E3 ligase activity—promoting Ras mono/di-ubiquitination, endosomal sequestration, and ERK suppression—unified the trafficking and signaling functions of Rabex-5.

    Evidence In vitro E3 assay with Ras, RIN1 epistasis, imaging of Ras endosomal relocalization (mammalian cells); Drosophila genetic epistasis with domain-specific transgenes

    PMID:20655224 PMID:20655225

    Open questions at the time
    • Ubiquitination sites on Ras not mapped
    • How RIN1 facilitates Rabex-5 access to Ras molecularly is unknown
  10. 2012 High

    Showing that the MIU domain recognizes ubiquitinated cargo (L1-CAM) for internalization and lysosomal targeting, and that GEF activity acts as an intramolecular switch on cargo binding, linked Rabex-5 to sorting of ubiquitinated transmembrane proteins.

    Evidence Co-IP of Rabex-5 with ubiquitinated L1, domain-mutant and GEF-mutant analysis of cargo binding and internalization kinetics

    PMID:22846990 PMID:23048039

    Open questions at the time
    • Structural basis for the GEF-MIU intramolecular switch not validated by structural methods
    • Generality beyond L1 not established
  11. 2015 Medium

    Genetic studies in Drosophila hematopoiesis and wing epithelium revealed Rabex-5 regulates Notch signaling in addition to Ras, through its E3 ligase domain, expanding the signaling repertoire of this protein.

    Evidence Tissue-specific knockdown and domain-specific transgenes in Drosophila, epistasis with Ras and Notch pathway mutants

    PMID:26567216 PMID:39466792

    Open questions at the time
    • Whether Rabex-5 directly ubiquitinates Notch or acts indirectly through endosomal sorting is unresolved
    • Mammalian relevance of Notch regulation not tested
  12. 2016 High

    Keratinocyte-specific deletion placing RABGEF1 upstream of IL-1R/MYD88/NF-κB signaling established it as a cell-intrinsic suppressor of innate immune activation in epithelial barriers.

    Evidence Keratinocyte-specific Cre-lox knockout, double KO epistasis with MYD88 and IL-1R1 restoring skin homeostasis

    PMID:27820702

    Open questions at the time
    • Molecular mechanism by which RABGEF1 suppresses MYD88 signaling (direct interaction vs. endosomal receptor turnover) not defined
    • Contribution of E3 vs. GEF activity to immune suppression not dissected
  13. 2019 High

    Extension of the epithelial immune-suppressive role to intestinal epithelial cells, with microbiota- and MYD88-dependent colitis upon RABGEF1 loss, confirmed a generalizable barrier-protective function.

    Evidence IEC-specific conditional KO, DSS and IL-10-deficiency colitis models, antibiotic depletion and MYD88 epistasis

    PMID:31628426

    Open questions at the time
    • Whether the endocytic defect in IECs is the direct cause of MYD88 hyperactivation remains correlative
    • Specific receptor(s) whose turnover is impaired not identified
  14. 2020 High

    Identifying Ras Tyr4 phosphorylation (by JAK2/SRC) as a prerequisite for Rabex-5-mediated ubiquitination provided a molecular switch linking receptor signaling intensity to Ras attenuation.

    Evidence Site-directed mutagenesis of Ras Y4, phosphomimic/phospho-dead alleles in cell-based ubiquitination and Drosophila in vivo analysis, in vitro kinase assays

    PMID:32559233

    Open questions at the time
    • In vivo phosphorylation of Ras Y4 at endogenous levels not demonstrated
    • Structural basis for phospho-Y4 recognition by Rabex-5 unknown
  15. 2024 Medium

    Discovery that RABGEF1 promotes TNF-induced necroptosis by inhibiting cIAP1 to accelerate RIPK1 phosphorylation and necrosome formation extended its role to programmed cell death.

    Evidence Co-IP of RABGEF1–cIAP1, overexpression and knockdown in L929 cells, Smac mimetic rescue, RIPK1 phosphorylation blotting

    PMID:38377943

    Open questions at the time
    • Whether RABGEF1 ubiquitinates cIAP1 directly not tested
    • Physiological relevance in vivo not demonstrated
    • Single cell-line system

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying structural and mechanistic model explaining how RABGEF1's GEF and E3 ligase activities are coordinately regulated at endosomal membranes, and the precise molecular mechanism by which it suppresses MYD88/NF-κB signaling in epithelial cells, remains unresolved.
  • No full-length Rabex-5 structure in complex with Rabaptin-5 or membrane
  • Molecular basis for MYD88/NF-κB suppression (direct target identity) unknown
  • Relative in vivo contributions of GEF vs. E3 activity to immune and Ras phenotypes not genetically separated in mammals

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4
Localization
GO:0005768 endosome 4 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 1
Partners
BIRC2CRBNHRASL1CAMRAB22ARAB5ARABEP1RIN1
Complex memberships
Rabaptin-5–Rabex-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) binding the canonical Ile44 hydrophobic patch (~29 µM affinity), and an A20 zinc-finger diaromatic patch binding a polar region centered on Asp58 of ubiquitin (~22 µM affinity). The A20 zinc finger also mediates intrinsic E3 ubiquitin ligase activity by directly recruiting a ubiquitin-loaded E2 conjugating enzyme. X-ray crystallography (2.5 Å), in vitro ubiquitin-binding assays, E3 ligase activity assays, mutagenesis Nature structural & molecular biology High 16462746
2006 Rabex-5 functions as an E3 ubiquitin ligase through its N-terminal A20-like Cys2/Cys2 zinc finger domain, undergoes monoubiquitination, and binds ubiquitin via an atypical ubiquitin-interacting motif (residues 1–76); the Rabex-5–Rabaptin-5 interaction is mediated by the 401–462 coiled-coil of Rabex-5 and the 551–661 coiled-coil of Rabaptin-5. In vitro E3 ligase assay, ubiquitin-binding assay, deletion mutagenesis, co-immunoprecipitation The Journal of biological chemistry High 16407276
2001 Rabaptin-5 stimulates the GDP/GTP exchange activity of Rabex-5 on Rab5; Rab5-dependent recruitment of Rabaptin-5 to early endosomes requires its physical association with Rabex-5; and the Rabaptin-5–Rabex-5 complex is essential for early endosome homotypic fusion, as demonstrated by reconstitution with recombinant proteins. Reconstitution with recombinant proteins, GEF activity assay, endosome fusion assay, membrane recruitment assay Molecular biology of the cell High 11452015
2001 Vps9p (yeast ortholog of Rabex-5) and Rabex-5 display weak nucleotide exchange activity on Ypt51p and Rab5, respectively, with a maximal rate constant for GDP release of ~0.01 s⁻¹, several orders of magnitude lower than other exchange factors, suggesting that GTPase cycling rate may be controlled at the exchange step. Quantitative in vitro GEF activity assay (kinetic analysis) Journal of molecular biology High 11419942
2003 GGA clathrin adaptors interact with the Rabaptin-5–Rabex-5 complex via a bipartite mechanism: GGA-GAE domains bind an FGPLV sequence (residues 439–443) in Rabaptin-5 (also recognized by gamma-adaptin ears), and GGA-GAT domains bind the C-terminal coiled-coils of Rabaptin-5. GGA-Rabaptin-5 interaction decreases clathrin binding to the GGA hinge, and GFP-Rabaptin-5 overexpression shifts GGA1 and cargo to enlarged early endosomes. Co-immunoprecipitation, GST pulldown, mutagenesis, fluorescence microscopy, overexpression The EMBO journal High 12505986
2008 Ubiquitin binding via the MIU/A20 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, suggesting a cycle of ubiquitin binding and monoubiquitination regulates endosomal association. Subcellular fractionation, domain-mutant rescue, live-cell imaging, immunofluorescence The EMBO journal High 18772883
2009 Rab22-GTP directly binds the early endosomal targeting (EET) domain (residues 81–230) of Rabex-5 to recruit it to early endosomes, establishing a Rab22–Rabex-5–Rab5 signaling relay that promotes early endosome fusion and EGF receptor endocytosis and degradation; Rab22 knockdown abrogates Rabex-5 membrane targeting. GST pulldown with GTPγS-loaded Rab22, shRNA knockdown, fluorescence microscopy, EGF degradation assay Molecular biology of the cell High 19759177
2007 Rabex-5 contains 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 association with early endosomes and Rab5 activation in vivo, independent of Rabaptin-5 binding; the GEF domain alone (135–399) lacks membrane-targeting ability. Deletion mutagenesis, fluorescence microscopy, dominant-negative Rab5 assay, in vivo Rab5 activation assay Molecular biology of the cell High 17699593
2010 Rabex-5 functions as an E3 ubiquitin ligase for Ras, promoting Ras mono- and di-ubiquitination; this ubiquitination drives Ras endosomal localization and suppresses ERK activation. The Ras effector RIN1 is required for Rabex-5-dependent Ras ubiquitination, suggesting a feedback mechanism coupling Ras activation to ubiquitination-mediated attenuation. In vitro E3 ligase assay, co-immunoprecipitation, endosomal localization imaging, ERK phosphorylation assay, RIN1 knockdown epistasis Current biology : CB High 20655225
2010 In Drosophila, Rabex-5 ubiquitin ligase activity (not its Rab5 GEF activity) is required to restrict Ras signaling during wing vein specification and to suppress oncogenic Ras eye phenotypes; genetic interaction experiments place Rabex-5 at the step of Ras, and tissue culture studies confirm Rabex-5 promotes Ras ubiquitination. Genetic epistasis (dominant-negative domain-specific transgenes), tissue culture ubiquitination assay, in vivo phenotypic analysis Current biology : CB High 20655224
2004 RabGEF1 binds to Ras and negatively regulates Ras activation and downstream effector pathways during FcεRI-dependent mast cell activation; RabGEF1-deficient mast cells show enhanced degranulation, lipid mediator release, and cytokine secretion, and knockout mice develop severe skin inflammation with increased mast cell numbers. Co-immunoprecipitation (RabGEF1–Ras), RabGEF1 knockout mouse, mast cell functional assays (degranulation, cytokine ELISA), in vivo skin histology Nature immunology High 15235600
2007 In RabGEF1-deficient mast cells, a functional Vps9/GEF domain (not the ZnF or coiled-coil domain) is required to correct abnormalities in IgE+Ag-induced degranulation, IL-6 production, and endosome fusion; the coiled-coil domain is required for Rabaptin-5 binding and maintenance of basal FcεRI surface expression; the ZnF domain has ubiquitin ligase activity. Lentiviral domain-mutant rescue in RabGEF1-/- mast cells, degranulation assay, cytokine ELISA, endosome fusion assay, flow cytometry, E3 ligase assay Blood High 17341663
2006 RabGEF1-deficient mast cells show enhanced and prolonged Ras and ERK activation after stem cell factor (SCF)/c-Kit stimulation, increased JNK activation, elevated Akt activation and survival advantage, and delayed c-Kit internalization; lentiviral rescue with wild-type RabGEF1 normalizes c-Kit internalization, confirming a positive role for RabGEF1 in c-Kit endocytic trafficking. RabGEF1 knockout mast cells, immunoblot for pERK/pJNK/pAkt, cytokine ELISA, lentiviral rescue, flow cytometry (c-Kit internalization) 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 addition to Rab5) in mouse hippocampal neurons, as identified by yeast two-hybrid with GDP-locked Rab17; 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, shRNA knockdown, fluorescence microscopy in hippocampal neurons The Journal of biological chemistry Medium 23430262
2012 Rabex-5 interacts with ubiquitinated neural cell adhesion molecule L1 via its MIU domain (not the A20 zinc finger) upon L1 clustering; this interaction depends on ubiquitin moieties on L1 and is required for internalization and lysosomal targeting of L1. Rabex-5 overexpression accelerates L1 internalization in an ubiquitination-dependent manner, while knockdown impairs it. Co-immunoprecipitation, domain-mutant analysis (MIU vs A20), shRNA knockdown, internalization assay, lysosomal trafficking assay The Journal of biological chemistry High 22846990
2012 The GEF activity of Rabex-5 acts as an intramolecular switch regulating the MIU domain's interaction with ubiquitinated cargo: GEF-impaired Rabex-5 mutants show increased flexibility in the HB-VPS9 hinge region, altered interaction with ubiquitinated L1, and increased catalytic efficiency leading to reduced cargo binding; monoubiquitination status of Rabex-5 is associated with cargo interaction. GEF mutant analysis, co-immunoprecipitation with ubiquitinated L1, structural flexibility analysis, monoubiquitination assay The Journal of biological chemistry Medium 23048039
2015 Rabaptin-5 membrane recruitment requires binding to both Rab4 and Rabex-5, but not Rab5; deletion of Rab5-binding domains or Rab5 silencing produces giant endosomes with mixed early/late identity rather than blocking Rabaptin-5 recruitment, contradicting the positive-feedback model and instead supporting a feed-forward model in which Rabaptin-5–Rabex-5 activates Rab5. Deletion analysis, RNAi knockdown, fluorescence microscopy, endosome characterization 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; loss of D2LR-Rabex-5 signaling reduces dendritic spine density and neuronal activity in striatopallidal medium spiny neurons. Co-immunoprecipitation (D2LR–Rabex-5), endosome imaging, Golgi transport assay, ERK phosphorylation, dendritic spine counting in D2LR knockout mice Molecular psychiatry Medium 27922607
2016 Keratinocyte-specific deletion of RABGEF1 causes aberrant activation of the IL-1R/MYD88/NF-κB signaling pathway, MYD88-dependent abnormalities in skin barrier structural proteins, and allergic skin and systemic inflammation; ablation of MYD88 or deletion of Il1r1 in RABGEF1-deficient keratinocytes restores skin homeostasis, placing RABGEF1 upstream of IL-1R/MYD88 signaling. Keratinocyte-specific conditional knockout (Cre-lox), MYD88/IL-1R1 double knockout epistasis, immunofluorescence for barrier proteins, cytokine measurement The Journal of clinical investigation High 27820702
2016 Cereblon forms a complex with Rabex-5; lenalidomide treatment prevents Cereblon–Rabex-5 association, while mutation of the IMiD-binding site of Cereblon increases co-immunoprecipitation with Rabex-5. Knockdown of Rabex-5 upregulates TLR-induced cytokine and type 1 IFN production via a STAT1/IRF pathway, identifying Rabex-5 as a negative regulator of TLR-activated innate signaling. Co-immunoprecipitation (Cereblon–Rabex-5), IMiD treatment, Rabex-5 knockdown in THP-1 cells, cytokine and IFN measurement Proceedings of the National Academy of Sciences of the United States of America Medium 27601648
2019 IEC-specific RABGEF1 deletion in mice impairs early endocytic events, increases p38 MAPK activation, and increases chemokine secretion in vitro; in vivo spontaneous colitis from RABGEF1-deficient IECs depends on microbiota-derived signals and intrinsic MYD88-dependent pathways, placing RABGEF1 as a suppressor of MYD88 signaling in intestinal epithelial cells. IEC-specific conditional KO, DSS and IL-10-deficiency colitis models, endosomal marker imaging, p38 MAPK immunoblot, cytokine ELISA, antibiotic depletion of microbiota Mucosal immunology High 31628426
2020 Rabex-5-mediated Ras ubiquitination requires Ras Tyrosine 4 (Y4): Y4-insensitive substitution mutants cannot undergo Rabex-5-mediated ubiquitination and display Ras gain-of-function phenotypes in vivo; Y4 phosphomimic substitution increases ubiquitination and suppresses oncogenic Ras phenotypes in a Rabex-5-dependent manner. JAK2 and SRC kinases can phosphorylate Ras at Y4 in vitro. Site-directed mutagenesis, cell-based ubiquitination assay, in vitro kinase assay (JAK2, SRC, EGFR), in vivo Drosophila genetic analysis, phospho-specific antibodies PLoS genetics High 32559233
2020 In retinal photoreceptors, RabGEF1 protein interacts with Rabaptin-5; its loss reduces early endosomes and causes abnormal accumulation of macromolecular aggregates in autophagosome-like vacuoles with enhanced LC3A/B and p62 immunostaining, indicating compromised autophagy and demonstrating an essential role for RabGEF1 in photoreceptor endocytic and autophagic homeostasis. Co-immunoprecipitation (RabGEF1–Rabaptin-5) in retina, Rabgef1-/- mouse, electron microscopy, immunostaining for autophagy markers, transcriptome analysis PLoS genetics Medium 33362196
2024 RABGEF1 promotes TNF-induced necroptosis by interacting with cIAP1 and inhibiting its function, thereby accelerating RIPK1 phosphorylation and necrosome formation; this pro-necrotic effect depends on both its E3 ubiquitin ligase activity and GEF activity, and can be abolished by the cIAP1 antagonist Smac mimetic SM-164. Co-immunoprecipitation (RABGEF1–cIAP1), overexpression and knockdown in L929 cells, RIPK1 phosphorylation immunoblot, Smac mimetic rescue Biochemical and biophysical research communications Medium 38377943
2024 In Drosophila wing epithelium, Rabex-5 requires an intact E3 ubiquitin ligase domain to inhibit Notch signaling; the Rab5 GEF domain alone suppresses Notch loss-of-function and enhances activated Ras and Notch gain-of-function phenotypes, indicating the GEF activity positively regulates both Ras and Notch signaling; Rabex-5 also inhibits overgrowth due to PTEN loss or PI3K activation but not AKT activation. Genetic epistasis with domain-specific transgenes (E3-impaired, GEF-impaired) in Drosophila, in vivo phenotypic analysis PloS one Medium 39466792
2015 In Drosophila, loss of Rabex-5 in hematopoietic cells causes hemocyte overproliferation, lymph gland enlargement, and melanotic mass formation; Ras activity mediates specific phenotypes while Ras-independent Notch protein accumulation in the lymph gland underlies distinct hematopoietic phenotypes, placing Rabex-5 as a coordinator of both Ras and Notch signaling in Drosophila hematopoiesis. Tissue-specific knockdown (hemocyte-specific), genetic epistasis with Ras/Notch pathway mutants, immunostaining for Notch protein Journal of cell science Medium 26567216
2015 RabGEF1 binds Rac1 and negatively regulates NGF-induced Rac1 activation in PC12 cells; RabGEF1 also interacts with NMDA receptor NR2B subunit and its binding partner SynGAP, and negatively regulates NMDA-induced nitric oxide synthase activation. Co-immunoprecipitation (RabGEF1–Rac1, RabGEF1–NR2B–SynGAP), antisense knockdown in PC12 cells, Rac1 activation assay, NOS activity assay PloS one Medium 26588713
2001 GST-Rab33b in its GTP-bound form interacts with both Rabaptin-5 and Rabex-5 (detected by Western blot/mass spectrometry), suggesting that the Rabex-5/Rabaptin-5 complex can function as an effector for Rab33b at the Golgi, extending Rabex-5's functional context beyond the endocytic pathway. GST pulldown with GTP-locked Rab33b, Western blot and mass spectrometry identification FEBS letters Low 11718716
2025 Rab21 competes with Rab5 for activation by Rabex-5; modulation of Rab5 or Rab21 dominant-negative mutant binding properties to Rabex-5 supports a model in which Rab21 may have higher affinity for Rabex-5 than Rab5 in vivo; Rab21 overexpression rescues EEA1 localization defects caused by PI3P depletion or Rab5 inhibition. Dominant-negative mutant analysis, overexpression rescue of endosomal defects, fluorescence microscopy 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 175 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 104 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 86 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 55 20655224
2004 RabGEF1 is a negative regulator of mast cell activation and skin inflammation. Nature immunology 53 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
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
2020 A conserved, N-terminal tyrosine signal directs Ras for inhibition by Rabex-5. PLoS genetics 10 32559233
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
2016 RABEX-5 overexpression in gastric cancer is correlated with elevated MMP-9 level. American journal of translational research 7 27347344
2019 Epithelial RABGEF1 deficiency promotes intestinal inflammation by dysregulating intrinsic MYD88-dependent innate signaling. Mucosal immunology 6 31628426
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 2 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