Affinage

EFNA3

Ephrin-A3 · UniProt P52797

Length
238 aa
Mass
26.4 kDa
Annotated
2026-06-09
21 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EFNA3 (LERK-3/EPLG3) encodes a GPI-anchored, membrane-bound ephrin-A ligand for Eph-related receptor tyrosine kinases, distinguishing it biochemically from the type-1 transmembrane ephrins (PMID:8660976). In tumor contexts it functions as a pro-progression effector: EphA3 binds EFNA3 and the resulting reverse signaling activates ERK1/2 to drive epithelial-to-mesenchymal transition and metastasis (PMID:40928719), while EFNA3 also engages PI3K/AKT/mTOR signaling to suppress autophagy and sustain proliferation, migration, and invasion (PMID:41763291). Consistent with a growth-promoting role, EFNA3 inhibits apoptosis in lung adenocarcinoma cells, with knockdown upregulating Bax and caspase-3 (PMID:35706812). EFNA3 expression is controlled at multiple regulatory layers: hypoxia drives HIF-dependent accumulation of EFNA3-locus lncRNAs and Ephrin-A3 protein to enhance breast cancer extravasation and metastasis (PMID:25023702); transcriptionally it is activated by hMAGEA2 promoter binding upstream of the Ras/Braf/MEK/ERK1/2 cascade (PMID:38925815) and by HOTTIP-recruited CTCF (PMID:36628218); post-transcriptionally it is stabilized by NSUN5-mediated m5C modification of its mRNA to support glycolysis (PMID:40730949); and it is repressed by multiple miRNAs including miR-210-3p, miR-423-5p, miR-365, and miR-326, the latter relieved by the ceRNA LINC01270 (PMID:32695810, PMID:36967852, PMID:38009813, PMID:35345980). In normal epithelial physiology, basal-cell-derived EFNA3 acts on luminal cells to enhance OXPHOS-driven collective migration and branching morphogenesis [PMID:bio_10.1101_2024.10.18.619009], and recombinant EFNA3 regulates desmosomal cadherin (DSG1) expression to maintain vaginal epithelial barrier function [PMID:bio_10.1101_2024.10.29.620915].

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 High

    Established the molecular identity of EFNA3 as a GPI-anchored ephrin ligand, defining the biochemical class through which it would later be understood to signal.

    Evidence Southern hybridization, FISH, genomic mapping and sequence analysis classifying LERK-3/EPLG3 as a GPI-anchored Eph receptor ligand

    PMID:8660976

    Open questions at the time
    • No receptor-specific binding kinetics or downstream signaling defined
    • Cellular and tissue functions not addressed
  2. 2013 Medium

    First placed EFNA3 downstream of a miRNA and gave it a pro-tumor function, showing miR-210 directly represses EFNA3 to limit proliferation and invasion.

    Evidence Luciferase reporter validation, qRT-PCR, Western blot and functional assays in MPNST cells

    PMID:24512729

    Open questions at the time
    • Signaling pathway downstream of EFNA3 not defined
    • Single tumor type
  3. 2014 Medium

    Connected EFNA3 to hypoxic signaling, showing HIF-driven EFNA3-locus lncRNAs raise Ephrin-A3 protein to promote breast cancer extravasation, decoupling protein accumulation from coding mRNA levels.

    Evidence HIF pathway manipulation, lncRNA characterization, protein measurement and extravasation assays in breast cancer cells

    PMID:25023702

    Open questions at the time
    • Molecular link between lncRNAs and protein accumulation not resolved
    • Receptor engagement during extravasation not characterized
  4. 2020 Medium

    Linked EFNA3 to PI3K/AKT signaling control in endothelial cells, showing ephrinA3 levels inversely regulate AKT phosphorylation and angiogenic behavior.

    Evidence Luciferase validation of miR-210-3p targeting, mimic/inhibitor transfection and phospho-AKT Western blot in HUVECs

    PMID:32695810

    Open questions at the time
    • Mechanism connecting EFNA3 to AKT not defined
    • Single cell system
  5. 2022 Medium

    Extended EFNA3 regulation to extracellular-vesicle miRNA delivery and additional transcriptional/loss-of-function contexts, establishing EFNA3 as a convergent node for angiogenesis, inflammation, and apoptosis control.

    Evidence miR-210-3p in hypoxic MSC-EVs (sequencing, in vivo bone model); HOTTIP/CTCF promoter recruitment by ChIP in asthma model; lentiviral knockdown with Bax/caspase-3 readout in LUAD; LINC01270 ceRNA sponging miR-326 in gastric cancer

    PMID:35345980 PMID:35706812 PMID:35850484 PMID:36628218

    Open questions at the time
    • Receptor-level signaling underlying these phenotypes not directly tested
    • Findings distributed across distinct disease models without unifying mechanism
  6. 2023 Medium

    Reinforced miRNA control of EFNA3 in non-cancer tissue, identifying miR-423-5p and miR-365 as repressors whose loss drives angiogenic and disc-degenerative phenotypes via EFNA3.

    Evidence Luciferase validation, EFNA3 overexpression rescue, and in vivo MI and IDD models

    PMID:36967852 PMID:38009813

    Open questions at the time
    • Downstream effectors of EFNA3 in these tissues not defined
  7. 2024 Medium

    Identified upstream transcriptional and post-transcriptional regulators (hMAGEA2 promoter binding; NSUN5 m5C mRNA modification) and revealed normal epithelial roles in OXPHOS-driven migration and desmosomal barrier maintenance, broadening EFNA3 beyond a tumor effector.

    Evidence Luciferase promoter assay and pathway knockdown (prostate cancer); MeRIP and glycolysis rescue (HCC); live imaging/OXPHOS measurement (mammary); recombinant EFNA3 dose-response in vivo (vaginal epithelium, preprint)

    PMID:38925815 PMID:40730949 PMID:bio_10.1101_2024.10.18.619009 PMID:bio_10.1101_2024.10.29.620915

    Open questions at the time
    • Two normal-physiology findings are preprints
    • Whether OXPHOS and barrier effects require Eph receptor engagement is untested
  8. 2025 Medium

    Provided direct receptor-level mechanism, confirming EphA3 binds EFNA3 and that reverse signaling activates ERK1/2 to drive EMT and metastasis.

    Evidence Co-immunoprecipitation, knockdown/overexpression, migration assays and mouse tumor models in colorectal cancer

    PMID:40928719

    Open questions at the time
    • Structural basis of binding not resolved
    • Single tumor type for reverse-signaling claim
  9. 2026 Medium

    Defined the autophagy-suppressing arm of EFNA3 signaling, showing knockdown activates autophagy and attenuates tumor growth via reduced PI3K/AKT/mTOR signaling.

    Evidence Knockdown with LC3 staining, TEM, pathway Western blot and xenograft model in breast cancer

    PMID:41763291

    Open questions at the time
    • Direct biochemical link from EFNA3 to PI3K/AKT/mTOR not established
    • Receptor dependence not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether EFNA3's forward (Eph receptor activation) versus reverse (ligand-side) signaling distinctly drive the ERK1/2, PI3K/AKT/mTOR, and OXPHOS outputs, and how its GPI-anchored ectodomain transmits these signals, remains unresolved.
  • No structural model of EFNA3-receptor complexes in the corpus
  • Mechanism converting receptor binding to intracellular ERK/AKT activation not defined
  • Receptor partners beyond EphA3 not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 1
Partners
EPHA3

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 Hypoxia induces HIF-mediated expression of long noncoding RNAs from the EFNA3 locus; these lncRNAs cause Ephrin-A3 protein accumulation (coding EFNA3 mRNA levels remain relatively stable), and sustained expression of both Ephrin-A3 and the EFNA3 lncRNAs increases metastatic potential of breast cancer cells, at least partly by increasing extravasation ability. HIF pathway manipulation, lncRNA characterization, breast cancer cell functional assays (extravasation), Western blot for protein levels Oncogene Medium 25023702
1996 EFNA3 (LERK-3/EPLG3) encodes a GPI-anchored membrane-bound ligand for Eph-related receptor tyrosine kinases (hek and elk), placing it in the GPI-anchored subgroup of ephrin ligands distinct from type-1 transmembrane ephrin members. Southern hybridization, FISH, genomic mapping, sequence analysis Genomics High 8660976
2020 EFNA3 is a direct target of miR-210-3p; ephrinA3 protein levels negatively regulate HUVEC migration and proliferation, and downregulation of ephrinA3 increases phosphorylated AKT, activating the PI3K/AKT pathway, while upregulation of ephrinA3 suppresses PI3K/AKT signaling. Luciferase reporter assay (miR-210-3p targeting EFNA3 3'UTR), miR-210-3p mimic/inhibitor transfection, Western blot for phospho-AKT, HUVEC migration/tube formation assays BioMed research international Medium 32695810
2013 miR-210 directly targets EFNA3 (validated by luciferase reporter assay) and regulates its mRNA and protein expression in MPNST cells; EFNA3 upregulation (when miR-210 is low) promotes proliferation and invasion of peripheral nerve sheath tumor cells. Luciferase reporter assay, qRT-PCR, Western blot, colony formation, cell cycle analysis, invasion assay Oncology research Medium 24512729
2022 miR-210-3p carried in hypoxic MSC-derived small extracellular vesicles suppresses EFNA3 expression and consequently activates the PI3K/AKT pathway to promote angiogenesis; HIF-1α drives miR-210-3p upregulation under hypoxia. miRNA sequencing, miR-210-3p mimic/inhibitor transfection, Western blot for EFNA3 and phospho-PI3K/AKT, HUVEC functional assays, calvarial bone defect in vivo model Acta biomaterialia Medium 35850484
2023 miR-423-5p delivered by hucMSC-derived extracellular vesicles inhibits EFNA3 expression; EFNA3 overexpression reverses the pro-angiogenic effects of these EVs on HUVEC migration and tube formation, establishing EFNA3 as a negative regulator of angiogenesis downstream of miR-423-5p. EV isolation/co-culture, miR-423-5p mimic transfection, EFNA3 overexpression rescue, HUVEC migration/tube formation assays, rat MI in vivo model Postepy w kardiologii interwencyjnej Medium 36967852
2025 EphA3 receptor binds to EFNA3 (confirmed by co-immunoprecipitation); EphA3/EFNA3 reverse signaling activates ERK1/2 signaling and promotes epithelial-to-mesenchymal transition (EMT) to facilitate colorectal cancer metastasis. Co-immunoprecipitation, EFNA3 knockdown and overexpression, transwell/wound healing assays, subcutaneous and spleen injection tumor models in nude mice, Western blot for EMT markers and phospho-ERK1/2 Digestive diseases and sciences Medium 40928719
2024 hMAGEA2 binds to the EFNA3 promoter region and transcriptionally regulates EFNA3 expression (confirmed by luciferase assay); EFNA3 downregulation upon hMAGEA2 knockdown reduces Ras/Braf/MEK/Erk1/2 phosphorylation, placing EFNA3 upstream of the Erk1/2 signaling cascade in prostate cancer. Luciferase reporter assay (EFNA3 promoter), hMAGEA2 knockdown stable cell lines, Western blot for Erk1/2 pathway components, proliferation/invasion/colony formation assays Anticancer research Medium 38925815
2022 The lncRNA HOTTIP promotes EFNA3 transcription by recruiting CTCF (CCCTC-binding factor) to the EFNA3 promoter; EFNA3 knockdown in vivo reduces OVA-induced airway inflammation in asthmatic mice, demonstrating EFNA3 as a downstream effector of HOTTIP-mediated inflammation. RNA pull-down, RNA immunoprecipitation, luciferase reporter assay, chromatin immunoprecipitation (ChIP), EFNA3 knockdown in OVA-mouse model, ELISA for inflammatory cytokines American journal of translational research Medium 36628218
2025 NSUN5 (an RNA m5C methyltransferase) promotes m5C modification of EFNA3 mRNA, stabilizing EFNA3 expression; EFNA3 overexpression rescues glycolysis inhibition caused by NSUN5 knockdown in liver hepatocellular carcinoma cells, placing EFNA3 downstream of NSUN5-mediated m5C modification in glycolysis regulation. Methylated RNA immunoprecipitation (MeRIP), dual-luciferase reporter assay, NSUN5 knockdown, EFNA3 overexpression rescue, glycolysis measurement, xenograft tumor model BMC cancer Medium 40730949
2022 EFNA3 knockdown in lung adenocarcinoma cells (A549 and PC9) reduces cell viability and proliferation, increases apoptosis, and upregulates apoptosis-related proteins Bax and caspase-3, demonstrating that EFNA3 promotes LUAD progression by inhibiting apoptosis. Lentiviral EFNA3 knockdown, MTT assay, ELISA for proliferation/apoptosis, RT-PCR and Western blot for Bax and caspase-3 Translational cancer research Low 35706812
2024 Topical administration of recombinant EFNA3 promotes vaginal DSG1 (desmoglein-1) expression in a biphasic dose-dependent manner and partially reverses loss of vaginal epithelial barrier function induced by progestin (DMPA) treatment in mice, identifying EFNA3 as a regulator of desmosomal cadherin gene expression in vaginal epithelium. Recombinant EFNA3 topical administration in mice, DSG1/DSC1 expression measurement, epithelial barrier function assay, HSV-2 infection model bioRxivpreprint Medium bio_10.1101_2024.10.29.620915
2024 Basal mammary epithelial cells produce EFNA3, which acts on luminal cells to enhance oxidative phosphorylation (OXPHOS) and energy production, thereby promoting collective epithelial migration and branching morphogenesis in vivo; inhibition of EFNA3 slows breast cancer metastasis. Live imaging of collective migration, EFNA3 inhibition/knockdown, OXPHOS measurement, in vivo mammary gland branching morphogenesis assay, breast cancer metastasis model bioRxivpreprint Medium bio_10.1101_2024.10.18.619009
2023 miR-365 directly targets EFNA3 (validated by luciferase reporter assay); EFNA3 upregulation in nucleus pulposus cells increases apoptosis and catabolic marker (MMP-13) expression while reducing collagen II and aggrecan, demonstrating EFNA3 as a pro-degenerative effector in intervertebral disc degeneration. Luciferase reporter assay, miR-365 mimic/inhibitor transfection, EFNA3 overexpression, apoptosis assay, immunofluorescence for ECM markers, rat IDD in vivo model Journal of cellular and molecular medicine Medium 38009813
2024 EFNA3 promotes choroidal melanoma cell growth and migration through activation of the Stat3/Akt signaling pathway; artesunate inhibits this tumor-promoting effect by downregulating EFNA3. EFNA3 knockdown, Western blot for Stat3/Akt pathway, clonogenic assay, CCK-8, transwell migration, xenograft tumor model Journal of cancer research and clinical oncology Low 38630320
2026 EFNA3 knockdown in breast cancer cells inhibits proliferation, migration, invasion and activates autophagy; mechanistically, EFNA3 activates the PI3K/AKT/mTOR pathway and suppresses autophagy, as confirmed in a xenograft model where EFNA3 knockdown reduces tumor growth, enhances autophagy markers, and reduces PI3K/AKT/mTOR signaling. EFNA3 knockdown, LC3 staining, TEM for autophagy, Western blot for PI3K/AKT/mTOR pathway, xenograft model, proliferation/apoptosis/invasion assays The international journal of biochemistry & cell biology Medium 41763291
2022 lncRNA LINC01270 acts as a competing endogenous RNA (ceRNA) by sponging miR-326, thereby positively regulating EFNA3 expression; EFNA3 overexpression rescues the anti-proliferative and anti-invasive effects of LINC01270 knockdown in gastric cancer cells. Luciferase reporter assay, RNA pull-down assay, LINC01270 knockdown, miR-326 inhibitor, EFNA3 overexpression rescue, CCK-8, colony formation, transwell assay Bioengineered Medium 35345980

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination. Oncogene 94 25023702
2022 Small extracellular vesicles derived from hypoxic mesenchymal stem cells promote vascularized bone regeneration through the miR-210-3p/EFNA3/PI3K pathway. Acta biomaterialia 83 35850484
2020 OSCC Exosomes Regulate miR-210-3p Targeting EFNA3 to Promote Oral Cancer Angiogenesis through the PI3K/AKT Pathway. BioMed research international 79 32695810
2013 MicroRNA-210 promotes proliferation and invasion of peripheral nerve sheath tumor cells targeting EFNA3. Oncology research 48 24512729
2018 Differentially expressed miRNA-210 during follicular-luteal transition regulates pre-ovulatory granulosa cell function targeting HRas and EFNA3. Journal of cellular biochemistry 20 29131373
2006 Expression analysis of the Epha1 receptor tyrosine kinase and its high-affinity ligands Efna1 and Efna3 during early mouse development. Gene expression patterns : GEP 16 16466970
2022 Hsa_circ_0007478 aggravates NLRP3 inflammasome activation and lipid metabolism imbalance in ox-LDL-stimulated macrophage via miR-765/EFNA3 axis. Chemico-biological interactions 15 36191606
1996 The genes encoding the eph-related receptor tyrosine kinase ligands LERK-1 (EPLG1, Epl1), LERK-3 (EPLG3, Epl3), and LERK-4 (EPLG4, Epl4) are clustered on human chromosome 1 and mouse chromosome 3. Genomics 13 8660976
2023 Extracellular vesicles derived from human umbilical cord mesenchymal stem cells stimulate angiogenesis in myocardial infarction via the microRNA-423-5p/EFNA3 axis. Postepy w kardiologii interwencyjnej = Advances in interventional cardiology 12 36967852
2024 Artesunate attenuates the tumorigenesis of choroidal melanoma via inhibiting EFNA3 through Stat3/Akt signaling pathway. Journal of cancer research and clinical oncology 10 38630320
2023 microRNA-365 attenuated intervertebral disc degeneration through modulating nucleus pulposus cell apoptosis and extracellular matrix degradation by targeting EFNA3. Journal of cellular and molecular medicine 8 38009813
2022 LncRNA LINC01270 aggravates the progression of gastric cancer through modulation of miR-326/EFNA3 axis. Bioengineered 8 35345980
2022 Long non-coding RNA HOTTIP induces inflammation in asthma by promoting EFNA3 transcription by CCCTC-binding factor. American journal of translational research 6 36628218
2018 Deletion of long noncoding RNA EFNA3 aggravates hypoxia-induced injury in PC-12 cells by upregulation of miR-101a. Journal of cellular biochemistry 6 30125989
2025 NSUN5 accelerates the progression of liver hepatocellular carcinoma by m5C-EFNA3-mediated glycolysis. BMC cancer 4 40730949
2022 The 1q21.3 region driver gene EFNA3 promotes disease progression via inhibition of lung adenocarcinoma cell apoptosis. Translational cancer research 2 35706812
2025 EphA3/EFNA3 Reverse Signalling Promotes Epithelial-to-Mesenchymal Transition via ERK Pathway to Facilitate Colorectal Cancer Metastasis. Digestive diseases and sciences 1 40928719
2026 EFNA3-mediated autophagy suppression drives breast cancer proliferation, EMT and metastasis via PI3K/AKT/mTOR axis. The international journal of biochemistry & cell biology 0 41763291
2026 Integrated multi-omics and machine learning identify EFNA3 as a key biomarker of tumor invasion. Frontiers in immunology 0 42004975
2025 Comprehensive analysis of Ephrin ligand and receptor expression reveals exclusive domains during nephrogenesis for epha4/epha7 and efna3. The International journal of developmental biology 0 41307306
2024 hMAGEA2 Accelerates the Progression of Prostate Cancer via the EFNA3-Erk1/2 Signaling Pathway. Anticancer research 0 38925815

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