Affinage

NGEF

Ephexin-1 · UniProt Q8N5V2

Length
710 aa
Mass
82.5 kDa
Annotated
2026-06-10
19 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NGEF (Ephexin1) is a neuronal Dbl-family guanine nucleotide exchange factor that activates Rho-type GTPases and couples receptor-level signaling to cytoskeletal and morphogenetic outputs (PMID:10777665). In Xenopus convergence and extension movements, NGEF functions downstream of RPTPα/PTPε phosphatases as a positive regulator of RhoA, since its knockdown disrupts these movements and is rescued by constitutively active RhoA (PMID:22545146). Through Eph receptor signaling NGEF directs axonal behavior: it promotes neurite outgrowth toward cancer cells via the Ephrin-A3/EphA2 axis, and in xenografts NGEF overexpression increases both tumor growth and nerve fiber density (PMID:40022166). In cancer, NGEF drives invasion and migration through epithelial-mesenchymal transition, and its expression is transcriptionally induced by BRAFV600E acting through the ERK/AP1 pathway (PMID:40703409). Independent of its GEF role, NGEF is required for polysome formation and supports mTOR-regulated translation of 5'-TOP and TOP-like mRNAs, such that its loss sensitizes tumors to mTOR inhibitors (PMID:40855114).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2000 Medium

    Established NGEF as a Dbl-family GEF for Rho GTPases with intrinsic transforming activity, defining its core molecular identity.

    Evidence Dbl-domain sequence analysis with cell transformation and nude mouse tumor induction assays

    PMID:10777665

    Open questions at the time
    • No direct biochemical demonstration of nucleotide exchange on a specific Rho GTPase
    • Upstream activators not identified at this stage
    • Transforming activity not linked to a defined substrate GTPase
  2. 2012 High

    Placed NGEF in a defined signaling pathway as a positive regulator of RhoA downstream of RPTPα/PTPε during morphogenetic cell movements, answering how NGEF GEF activity is wired into development.

    Evidence Morpholino knockdown in Xenopus with constitutively active RhoA rescue and dominant-negative controls

    PMID:22545146

    Open questions at the time
    • Mechanism by which phosphatases regulate NGEF activity not resolved
    • Direct biochemical GEF assay on RhoA not shown in this system
  3. 2025 Medium

    Linked NGEF to Eph receptor-mediated axon guidance in a tumor microenvironment, showing it drives neurite outgrowth and tumor nerve infiltration via Ephrin-A3/EphA2.

    Evidence Neuron-cancer co-culture with Ephrin-A3 knockdown and EphA2 inhibition, plus mouse xenograft with nerve fiber quantification

    PMID:40022166

    Open questions at the time
    • Whether GEF/RhoA activity mediates this neurite effect not tested
    • Direct physical interaction of NGEF with EphA2 not demonstrated
    • Single lab, limited orthogonal validation
  4. 2025 Medium

    Revealed a GEF-independent role for NGEF in translation, identifying it as essential for polysome assembly and mTOR-regulated TOP mRNA translation with therapeutic synthetic-lethal implications.

    Evidence Polysome profiling and expression analysis after knockdown, plus xenograft mTOR inhibitor combination

    PMID:40855114

    Open questions at the time
    • Molecular mechanism connecting NGEF to polysome assembly unknown
    • No structural or biochemical basis for TOP-mRNA selectivity
    • Relationship to its Rho-GEF function unresolved
  5. 2025 Medium

    Defined NGEF as a transcriptional effector of oncogenic BRAF signaling driving cancer cell invasion through EMT.

    Evidence Invasion/migration and EMT biomarker assays, ERK/AP1 pathway inhibition, and dual-luciferase reporter assays in BRAFV600E models

    PMID:40703409

    Open questions at the time
    • Direct AP1 binding site in the NGEF promoter not mapped beyond reporter assay
    • Whether GEF activity is required for the invasive phenotype not tested
  6. 2025 Low

    Associated NGEF variants with idiopathic scoliosis and positioned it downstream of EPHA4 in spinal patterning.

    Evidence Human genetic variant analysis in idiopathic scoliosis cohorts with inferred pathway placement

    PMID:40662934

    Open questions at the time
    • Genetic association only, no direct functional test of NGEF variants
    • EPHA4-NGEF pathway link inferred rather than experimentally tested
    • Causality for scoliosis not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NGEF's canonical Rho-GEF activity mechanistically relates to its distinct translational and Eph-receptor-coupled roles, and which substrate GTPases operate in each context, remains unresolved.
  • No unifying mechanism connecting GEF, translation, and Eph signaling roles
  • Direct GTPase substrate specificity not biochemically defined across contexts

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 NGEF was identified as a novel member of the Dbl family of guanine nucleotide exchange factors (GEFs), capable of acting as a GEF for Rho-type GTPases. It demonstrated transforming potential in cell culture and ability to induce tumors in nude mice, consistent with GEF/RhoGTPase signaling activity. Sequence analysis (Dbl family domain identification), cell transformation assay, nude mouse tumor induction Genomics Medium 10777665
2012 In Xenopus convergence and extension cell movements, NGEF acts downstream of RPTPα/PTPε phosphatases to promote RhoA activation. Morpholino knockdown of NGEF disrupted convergence and extension, and this phenotype was rescued by constitutively active RhoA, placing NGEF as a positive regulator of RhoA in this pathway. Morpholino knockdown in Xenopus embryos, epistasis with constitutively active/dominant-negative RhoA rescue, co-knockdown specificity controls PloS one High 22545146
2025 NGEF (Ephexin1) promotes axonal growth in neurons co-cultured with lung cancer cells via the Ephrin-A3/EphA2 pathway. Knockdown of Ephrin-A3 in neurons or inhibition of EphA2 with ALW-II-41-27 blocked neurite outgrowth stimulated by NGEF-overexpressing cancer cells. In a mouse xenograft model, NGEF overexpression increased tumor growth and nerve fiber density, effects inhibited by ALW-II-41-27. Co-culture experiments (neurons + cancer cells), Ephrin-A3 knockdown, EphA2 inhibitor (ALW-II-41-27), mouse subcutaneous xenograft model with nerve fiber density quantification Journal of translational medicine Medium 40022166
2025 Ephexin1/NGEF is essential for polysome formation and promotes translation of mRNAs containing 5'-terminal oligopyrimidine (TOP) or 5'-TOP-like motifs, acting as a key mediator of mTOR-regulated translation. Ephexin1 deficiency enhanced efficacy of mTOR inhibitors in a mouse xenograft lung cancer model, indicating synthetic lethality. Polysome profiling, gene expression analysis after NGEF knockdown, mouse xenograft model with mTOR inhibitor combination Experimental & molecular medicine Medium 40855114
2025 NGEF promotes invasion and migration of BRAFV600E-mutant thyroid cancer cells through the epithelial-mesenchymal transition (EMT) pathway. NGEF expression is transcriptionally regulated by BRAFV600E via the ERK/AP1 pathway, as confirmed by pathway inhibition experiments and dual-luciferase reporter assays. Functional invasion/migration assays, EMT biomarker analysis, pathway inhibition, dual-luciferase reporter assay, BRAFV600E-engineered cellular models Biochemistry and biophysics reports Medium 40703409
2025 Variants in NGEF were identified in cases of idiopathic scoliosis (IS), and NGEF is positioned as a downstream molecule in the EPHA4 signaling pathway relevant to spinal patterning, based on analysis of IS cohort data. Human genetic variant analysis in IS cohorts; pathway placement as downstream of EPHA4 based on known pathway membership eLife Low 40662934

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Candidate downstream regulated genes of HOX group 13 transcription factors with and without monomeric DNA binding capability. Developmental biology 51 15733672
2016 A panel of four genes accurately differentiates benign from malignant thyroid nodules. Journal of experimental & clinical cancer research : CR 37 27793213
2012 3T3 cell lines stably expressing Pax6 or Pax6(5a)--a new tool used for identification of common and isoform specific target genes. PloS one 29 22384097
2000 Characterization of Ngef, a novel member of the Dbl family of genes expressed predominantly in the caudate nucleus. Genomics 26 10777665
2010 Analyses of porcine public SNPs in coding-gene regions by re-sequencing and phenotypic association studies. Molecular biology reports 22 21107721
2022 Regulation of the COPII secretory machinery via focal adhesions and extracellular matrix signaling. The Journal of cell biology 13 35829701
2021 Identification of Potential BRAF Inhibitor Joint Therapy Targets in PTC based on WGCAN and DCGA. Journal of Cancer 11 33613767
2012 Pair-wise regulation of convergence and extension cell movements by four phosphatases via RhoA. PloS one 9 22545146
2022 Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE). Cancers 8 36139690
2024 Identification of biomarkers and immune microenvironment associated with pterygium through bioinformatics and machine learning. Frontiers in molecular biosciences 6 39722894
2020 Genetic background and diet affect brown adipose gene coexpression networks associated with metabolic phenotypes. Physiological genomics 5 32338175
2024 A systems biology-based identification and in vivo functional screening of Alzheimer's disease risk genes reveal modulators of memory function. Neuron 4 38692279
2025 EPHA4 signaling dysregulation links abnormal locomotion and the development of idiopathic scoliosis. eLife 3 40662934
2016 Proinflammatory responses driven by non-gluten factors are masked when they appear associated to gliadins. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 3 27377345
2025 Neuronal guanine nucleotide exchange factor promotes the axonal growth and cancer cell proliferation via Ephrin-A3/EphA2 axis in lung adenocarcinoma. Journal of translational medicine 2 40022166
2019 Association of MAD1L1 polymorphism (rs871925) with prenatal famine exposure and schizophrenia in a Chinese population: A case-control study. IUBMB life 2 31498969
2025 The role of Ephexin1 in translation and mTOR-targeted cancer therapy. Experimental & molecular medicine 1 40855114
2026 Integrating network toxicology and experimental validation to elucidate the molecular mechanism basis of chondrotoxicity of Benzo[a]pyrene in osteoarthritis. Ecotoxicology and environmental safety 0 42034589
2025 Up-regulation of NGEF via the BRAFV600E /ERK/AP1 pathway enhances invasion and migration abilities of BRAFV600E-mutant thyroid cancer. Biochemistry and biophysics reports 0 40703409

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