Affinage

RASGEF1B

Ras-GEF domain-containing family member 1B · UniProt Q0VAM2

Length
473 aa
Mass
55.4 kDa
Annotated
2026-06-10
11 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RASGEF1B is a guanine nucleotide exchange factor that links innate immune signaling to small-GTPase activation and, independently, restrains tumor progression through a metabolic-epigenetic axis (PMID:19645719, PMID:41742192). As a GEF it is highly specific for the Rap-subfamily GTPase Rap2 and does not act on Rap1 or other Ras-family members, with Phe39 in the Rap2 switch I region serving as the specificity determinant (PMID:19645719). The protein localizes to early endosomes, where it associates with and activates Ras-like proteins, and its expression is induced in macrophages downstream of TLR3 and TLR4 via the TRIF (MyD88-independent) pathway (PMID:20090772). This induction is driven transcriptionally by NF-κB: RelA and cRel are recruited to a proximal promoter cluster of κB sites to activate Rasgef1b in response to LPS (PMID:32866686). Loss of Rasgef1b in mice reshapes macrophage transcriptional programs governing chemotaxis, cytokine responses, and GTPase regulation, and produces neurochemical and behavioral abnormalities including altered dopamine/serotonin receptor expression and reduced hippocampal BDNF (PMID:37950057, PMID:38048936). In hepatocellular carcinoma, RASGEF1B competitively protects ALDH7A1 from BMI1-mediated ubiquitination, raising betaine levels that promote SNAI1 DNA methylation and thereby suppress epithelial-mesenchymal transition (PMID:41742192).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2009 High

    Established the core enzymatic identity of RASGEF1B by defining its substrate specificity, answering whether it is a general Ras GEF or a selective one.

    Evidence In vitro nucleotide exchange assays with purified proteins plus reciprocal switch I mutagenesis of Rap1/Rap2

    PMID:19645719

    Open questions at the time
    • Physiological context in which Rap2 activation by RASGEF1B occurs not addressed
    • Regulation of GEF activity (autoinhibition, recruitment) not characterized
  2. 2010 Medium

    Connected the GEF to a subcellular site and an immune signaling input, showing where it acts and how its expression is triggered.

    Evidence Subcellular fractionation and confocal co-localization in HEK293T, live-cell Ras activity assay, and MyD88/TRIF knockout macrophage infection models

    PMID:20090772

    Open questions at the time
    • Localization shown for ectopically expressed protein, not endogenous
    • Ras activation observed but reconciliation with Rap2-specific in vitro activity unresolved
  3. 2020 High

    Defined the transcriptional mechanism of TLR-induced expression, identifying the specific factors and promoter elements driving induction.

    Evidence Luciferase reporters, κB-site mutagenesis, ATAC-seq, ChIP-seq, Rela-deficient macrophages, and pharmacological NF-κB inhibition

    PMID:32866686

    Open questions at the time
    • Downstream consequences of induced RASGEF1B on macrophage GTPase signaling not traced
    • Relative contributions of RelA versus cRel in vivo not resolved
  4. 2023 Medium

    Tested the organism-level requirement for RASGEF1B, revealing its impact on macrophage gene regulation and a specific promoter target.

    Evidence RNA-seq of wild-type vs. knockout BMDMs with RT-qPCR validation and Serpinb2 promoter luciferase assay under knockdown

    PMID:37950057

    Open questions at the time
    • Mechanism linking GEF activity to Serpinb2 promoter regulation not defined
    • Direct versus indirect transcriptional effects not separated
  5. 2023 Medium

    Extended the phenotypic role of RASGEF1B beyond immunity to the nervous system, documenting behavioral and neurochemical consequences of its loss.

    Evidence Conditional knockout mouse with behavioral testing, RT-qPCR of neurotransmitter receptors, microglial morphometry, and BDNF quantification

    PMID:38048936

    Open questions at the time
    • No direct mechanistic link from GEF/Rap2 activity to neurochemical phenotypes
    • Cell-type origin of behavioral defects (neuronal vs. microglial) not resolved
  6. 2026 High

    Uncovered a non-canonical tumor-suppressive function, showing RASGEF1B operates through protein stabilization and metabolic reprogramming rather than its GEF activity.

    Evidence Co-IP, GST pull-down, in vitro reconstituted ubiquitination, cycloheximide chase, methylation-specific PCR, metabolomics, and in vitro/in vivo HCC models

    PMID:41742192

    Open questions at the time
    • Whether GEF/Rap2 activity contributes to ALDH7A1 protection not determined
    • Structural basis of competition with BMI1 for ALDH7A1 not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RASGEF1B's Rap2-specific GEF activity, endosomal localization, and tumor-suppressive ALDH7A1-stabilizing function mechanistically integrate within a single protein remains unresolved.
  • No unifying mechanism connecting GEF activity to ALDH7A1 stabilization
  • Endogenous interactome and structure not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1
Localization
GO:0005768 endosome 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-162582 Signal Transduction 2
Partners
ALDH7A1BMI1RAP2RELA

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 RasGEF1B functions as a highly specific guanine nucleotide exchange factor (GEF) for Rap2, a member of the Rap subfamily of Ras-like G-proteins, but does not act on Rap1 or other Ras subfamily members. Reciprocal site-directed mutagenesis identified Phe39 in the switch I region of Rap2 as the specificity determinant; mutating the corresponding Ser39 in Rap1 to Phe (Rap1-S39F) allowed RasGEF1B to stimulate nucleotide exchange on Rap1. In vitro nucleotide exchange assays with purified RasGEF1B and Ras-family proteins; reciprocal site-directed mutagenesis of Rap1/Rap2 switch I residues The FEBS journal High 19645719
2010 RasGEF1B localizes to early endosomes when ectopically expressed in HEK293T cells (found predominantly in the heavy membrane fraction by fractionation and confirmed at early endosomes by confocal microscopy). RasGEF1B was found in close association with Ras in live cells and triggered Ras GTPase activity, indicating it can activate Ras-like proteins at early endosomes. In macrophages, TLR3 (poly I:C) and TLR4 (LPS) induce RasGEF1B expression through the MyD88-independent (TRIF) pathway. Subcellular fractionation, confocal microscopy co-localization, live-cell Ras activity assay; in vivo infection models with MyD88/TRIF knockout macrophages Genes and immunity Medium 20090772
2020 TLR-induced transcription of Rasgef1b in macrophages is driven by NF-κB acting through a proximal promoter region (-183 to +119) that contains a cluster of five NF-κB binding sites. Site-directed mutagenesis of these κB sites reduced maximal LPS-induced promoter activation. ChIP-seq showed RelA (p65) is recruited to this promoter region upon LPS stimulation. Rela-deficient macrophages or pharmacological NF-κB inhibition (Bay11-7082) reduced optimal Rasgef1b expression, and luciferase reporter assays showed RelA and cRel (but not RelB) activate the promoter. Luciferase reporter assay, site-directed mutagenesis of κB sites, ATAC-seq, ChIP-seq, Rela-deficient macrophages, pharmacological inhibition The international journal of biochemistry & cell biology High 32866686
2023 Deletion of Rasgef1b in mice alters basal and LPS-induced expression of genes involved in chemotaxis, cytokine responses, and GTPase activity regulation in macrophages. RasGEF1b knockdown in RAW264.7 macrophages impaired transcriptional activation of the Serpinb2 promoter both under constitutive and LPS-stimulated conditions, as demonstrated by luciferase reporter assay. RNA-seq transcriptomics in wild-type vs. Rasgef1b-knockout bone marrow-derived macrophages; RT-qPCR validation; luciferase-based Serpinb2 promoter assay with RasGEF1b knockdown Scientific reports Medium 37950057
2023 RasGEF1b deficiency in mice leads to behavioral abnormalities (hyperlocomotion, anhedonia, compulsive-like behavior reversible by fluoxetine), downregulation of dopamine receptor (Drd1, Drd2, Drd4, Drd5) and serotonin receptor (5Htr1a, 5Htr1b, 5Htr1d) mRNAs in hippocampus and prefrontal cortex, morphological alterations in microglia, and decreased hippocampal BDNF levels. Conditional knockout mouse model; behavioral tests; RT-qPCR for receptor mRNAs; microglia morphological analysis; BDNF protein quantification Progress in neuro-psychopharmacology & biological psychiatry Medium 38048936
2026 RASGEF1B suppresses hepatocellular carcinoma through a metabolic–epigenetic axis: RASGEF1B competitively protects ALDH7A1 protein from BMI1-dependent ubiquitination (confirmed by co-immunoprecipitation, GST pull-down, and in vitro reconstituted ubiquitination assay), thereby elevating cellular betaine levels. Elevated betaine promotes SNAI1 DNA methylation via methionine metabolic reprogramming, reducing SNAI1 expression and suppressing epithelial-mesenchymal transition and HCC progression. Co-immunoprecipitation, GST pull-down, immunofluorescence, in vitro reconstituted ubiquitination system, cycloheximide chase, methylation-specific PCR, luciferase reporter assay, transcriptome sequencing, untargeted metabolomics, in vitro and in vivo tumor models Journal of translational medicine High 41742192

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Inducible RasGEF1B circular RNA is a positive regulator of ICAM-1 in the TLR4/LPS pathway. RNA biology 135 27362560
2017 Transcriptomic analysis of the role of RasGEF1B circular RNA in the TLR4/LPS pathway. Scientific reports 34 28947785
2009 RasGEF1A and RasGEF1B are guanine nucleotide exchange factors that discriminate between Rap GTP-binding proteins and mediate Rap2-specific nucleotide exchange. The FEBS journal 29 19645719
2010 Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor. Genes and immunity 23 20090772
2006 Expression of rasgef1b in zebrafish. Gene expression patterns : GEP 20 17239665
2023 Aberrant expression of circular RNA DHPR facilitates tumor growth and metastasis by regulating the RASGEF1B/RAS/MAPK axis in hepatocellular carcinoma. Cellular oncology (Dordrecht, Netherlands) 14 37099250
2020 Toll-like Receptor (TLR)-induced Rasgef1b expression in macrophages is regulated by NF-κB through its proximal promoter. The international journal of biochemistry & cell biology 13 32866686
2021 Circ_RASGEF1B Promotes LPS-Induced Apoptosis and Inflammatory Response by Targeting MicroRNA-146a-5p/Pdk1 Axis in Septic Acute Kidney Injury Cell Model. Nephron 11 34438395
2023 Transcriptomic analysis reveals that RasGEF1b deletion alters basal and LPS-induced expression of genes involved in chemotaxis and cytokine responses in macrophages. Scientific reports 4 37950057
2023 Behavioral, neurochemical and neuroimmune features of RasGEF1b deficient mice. Progress in neuro-psychopharmacology & biological psychiatry 3 38048936
2026 RASGEF1B suppresses hepatocellular carcinoma through the ALDH7A1/Betaine/SNAI1 metabolic‒epigenetic axis. Journal of translational medicine 0 41742192

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