Affinage

EFNA3

Ephrin-A3 · UniProt P52797

Length
238 aa
Mass
26.4 kDa
Annotated
2026-04-28
21 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EFNA3 encodes a GPI-anchored ligand for Eph receptor tyrosine kinases that mediates bidirectional signaling to regulate angiogenesis, epithelial-to-mesenchymal transition, autophagy, and cellular metabolism (PMID:8660976, PMID:40928719, PMID:41763291). Upon engagement with EphA3, EFNA3 reverse signaling activates ERK1/2 to drive EMT and metastasis in colorectal cancer, while in breast cancer it activates PI3K/AKT/mTOR signaling to suppress autophagy and promote proliferation (PMID:40928719, PMID:41763291). EFNA3 expression is transcriptionally regulated by hypoxia-induced lncRNAs from its own locus, by CTCF recruited via lncRNA HOTTIP, and by hMAGEA2, and is post-transcriptionally controlled by multiple miRNAs (miR-210-3p, miR-423-5p, miR-326, miR-365, miR-765) and by NSUN5-mediated m5C mRNA methylation that stabilizes the transcript (PMID:25023702, PMID:36628218, PMID:38925815, PMID:32695810, PMID:40730949). Downregulation of EFNA3 by miR-210-3p or miR-423-5p relieves its tonic suppression of PI3K/AKT signaling in endothelial cells, thereby promoting angiogenesis (PMID:32695810, PMID:35850484, PMID:36967852).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1996 High

    The molecular identity of EFNA3 was established as a GPI-anchored ligand for Eph receptor tyrosine kinases, placing it within the ephrin-A family and providing the chromosomal assignment (1q21-q22).

    Evidence Southern hybridization of somatic cell hybrids, FISH, and structural characterization of GPI linkage

    PMID:8660976

    Open questions at the time
    • No cognate receptor specificity profile determined beyond hek/elk
    • No functional signaling readout measured
    • No tissue-specific expression pattern characterized
  2. 2014 Medium

    The question of how EFNA3 expression is controlled under pathophysiological conditions was addressed by showing that hypoxia-induced, HIF-dependent lncRNAs transcribed from the EFNA3 locus cause Ephrin-A3 protein accumulation and enhance metastatic extravasation, establishing EFNA3 as a hypoxia-responsive effector of metastasis.

    Evidence lncRNA identification, HIF reporter assays, protein measurements under hypoxia, and in vivo extravasation assays in breast cancer models

    PMID:25023702

    Open questions at the time
    • Mechanism by which lncRNA increases protein without changing coding mRNA levels is not resolved
    • No identification of the downstream receptor engaged during extravasation
  3. 2013 Medium

    EFNA3 was identified as a direct target of miR-210, establishing the first post-transcriptional regulatory axis controlling EFNA3 and linking its expression to tumor cell proliferation and invasion.

    Evidence Luciferase reporter assay for miR-210/EFNA3 3′-UTR, qRT-PCR, Western blot, and functional assays in MPNST cells

    PMID:24512729

    Open questions at the time
    • Downstream signaling pathway through which EFNA3 drives MPNST proliferation not identified
    • No receptor engagement demonstrated in this system
  4. 2020 Medium

    The downstream signaling consequence of EFNA3 suppression was resolved: miR-210-3p-mediated downregulation of EFNA3 activates PI3K/AKT signaling in endothelial cells to promote angiogenesis, establishing EFNA3 as a tonic suppressor of the PI3K/AKT pathway.

    Evidence Luciferase reporter validation, miR-210-3p mimic/inhibitor, Western blot for phospho-AKT, tube formation assays in HUVECs

    PMID:32695810

    Open questions at the time
    • Whether EFNA3 inhibits PI3K/AKT through a specific Eph receptor or an alternative mechanism is unknown
    • No structural or biochemical basis for EFNA3-mediated AKT suppression
  5. 2022 Medium

    The miR-210-3p/EFNA3/PI3K-AKT axis was independently replicated in a bone regeneration context, and additional miRNA regulators (miR-765, miR-326) were shown to converge on EFNA3 to modulate inflammasome activation and cancer proliferation, broadening the functional repertoire of EFNA3 regulation.

    Evidence In vivo calvarial bone defect model with HIF-1α/miR-210-3p/EFNA3 axis (PMID:35850484); circRNA/miR-765/EFNA3/NLRP3 axis in macrophages (PMID:36191606); LINC01270/miR-326/EFNA3 axis in gastric cancer (PMID:35345980)

    PMID:35345980 PMID:35850484 PMID:36191606

    Open questions at the time
    • Mechanism by which EFNA3 activates NLRP3 inflammasome is not defined
    • LINC01270/miR-326 axis is single-lab without replication
    • No direct EFNA3-receptor interaction demonstrated in macrophage or gastric cancer systems
  6. 2022 Medium

    A new layer of transcriptional regulation was uncovered: lncRNA HOTTIP recruits the chromatin architectural factor CTCF to the EFNA3 promoter, activating EFNA3 transcription and driving airway inflammation in asthma.

    Evidence RNA pull-down, RNA immunoprecipitation, ChIP, luciferase reporter, and OVA-induced asthma mouse model with EFNA3 knockdown

    PMID:36628218

    Open questions at the time
    • Which Eph receptor transduces EFNA3 signaling in airway epithelium is unknown
    • No independent replication of HOTTIP-CTCF-EFNA3 axis
  7. 2023 Medium

    EFNA3 was shown to promote apoptosis and extracellular matrix degradation in nucleus pulposus cells, with miR-365-mediated suppression of EFNA3 protecting against intervertebral disc degeneration, extending EFNA3 function to musculoskeletal homeostasis.

    Evidence Luciferase reporter, miR-365 mimic/inhibitor, flow cytometry, immunofluorescence, rat IDD model

    PMID:38009813

    Open questions at the time
    • Downstream pathway linking EFNA3 to MMP-13 expression and apoptosis not identified
    • Single lab with no independent confirmation
  8. 2023 Medium

    The miR-423-5p/EFNA3 axis was identified as a second endothelial angiogenesis-regulatory circuit, with extracellular vesicle delivery of miR-423-5p suppressing EFNA3 to promote vascularization after myocardial infarction.

    Evidence EV isolation, miR-423-5p mimic, EFNA3 overexpression rescue, HUVEC functional assays, rat MI model with capillary density measurement

    PMID:36967852

    Open questions at the time
    • Specific Eph receptor interaction mediating EFNA3 anti-angiogenic effect not resolved
    • Single lab, no independent replication
  9. 2024 Medium

    The transcription factor hMAGEA2 was shown to directly bind the EFNA3 promoter and activate transcription, with elevated EFNA3 driving Ras/Braf/MEK/ERK1/2 signaling to promote prostate cancer aggressiveness, identifying a new transcriptional activator and the MAPK cascade as a major EFNA3 effector pathway.

    Evidence Dual-luciferase reporter for promoter binding, Western blot for ERK1/2 phosphorylation, hMAGEA2 knockdown, proliferation/invasion assays

    PMID:38925815

    Open questions at the time
    • Whether hMAGEA2 binds EFNA3 promoter directly or through a co-factor is not resolved biochemically
    • No receptor engagement shown in prostate cancer cells
  10. 2025 Medium

    The first direct physical interaction between EFNA3 and EphA3 was confirmed, and reverse signaling through EFNA3 was shown to activate ERK1/2 to drive EMT and colorectal cancer metastasis, establishing a receptor-ligand pair and directionality of signaling.

    Evidence Co-immunoprecipitation, EFNA3 knockdown/overexpression, EMT and ERK1/2 Western blot, subcutaneous and spleen injection tumor models in nude mice

    PMID:40928719

    Open questions at the time
    • Reverse signaling mechanism through a GPI-anchored ligand (which lacks cytoplasmic domain) is not biochemically resolved — likely requires co-receptor
    • Single Co-IP without reciprocal validation explicitly described
  11. 2025 Medium

    EFNA3 mRNA was found to be stabilized by NSUN5-mediated m5C modification, and stabilized EFNA3 promotes aerobic glycolysis in hepatocellular carcinoma, revealing an epitranscriptomic layer of regulation.

    Evidence MeRIP for m5C, dual-luciferase reporter, NSUN5 knockdown with EFNA3 rescue, glycolysis measurements in vitro and xenograft model

    PMID:40730949

    Open questions at the time
    • Specific m5C site(s) on EFNA3 mRNA not mapped at single-nucleotide resolution
    • How EFNA3 protein mechanistically promotes glycolysis is undefined
  12. 2026 Medium

    EFNA3 was shown to activate PI3K/AKT/mTOR signaling, suppress autophagy, and promote EMT and metastasis in breast cancer, integrating its roles in proliferation, survival, and metabolic reprogramming into a unified oncogenic signaling model.

    Evidence EFNA3 knockdown/overexpression, Western blot for PI3K/AKT/mTOR phosphorylation, LC3 staining, TEM for autophagosomes, xenograft mouse model

    PMID:41763291

    Open questions at the time
    • Whether autophagy suppression is a direct consequence of mTOR activation or involves additional EFNA3-dependent mechanisms is unclear
    • Receptor mediating PI3K/AKT/mTOR activation in breast cancer not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EFNA3, a GPI-anchored protein lacking a cytoplasmic domain, transduces reverse signals to activate ERK1/2 and PI3K/AKT/mTOR pathways remains mechanistically unresolved — the identity of the co-receptor or transmembrane adaptor mediating intracellular signal propagation is unknown.
  • Co-receptor or transmembrane adaptor for reverse signaling not identified
  • No structural model of EFNA3-EphA3 complex exists
  • Relative contributions of forward versus reverse signaling in each disease context remain unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1643685 Disease 6 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 2 GO:0005576 extracellular region 1 R-HSA-9612973 Autophagy 1
Partners
CTCFEPHA3NSUN5

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 novel long noncoding RNAs from the EFNA3 locus, which cause Ephrin-A3 protein accumulation (without changing coding EFNA3 mRNA levels), and both the lncRNAs and Ephrin-A3 increase the metastatic potential of breast cancer cells by enhancing extravasation lncRNA identification, HIF reporter assays, protein level measurements under hypoxia, in vivo extravasation/metastasis assays Oncogene Medium 25023702
2020 EFNA3 is a direct target of miR-210-3p; downregulation of Ephrin-A3 protein in HUVECs activates the PI3K/AKT pathway, promoting angiogenesis, while upregulation of EFNA3 suppresses PI3K/AKT signaling and inhibits HUVEC migration and proliferation Luciferase reporter assay (target validation), miR-210-3p mimic/inhibitor transfection, Western blot for phosphorylated AKT, tube formation assay, exosome transfer experiments BioMed research international Medium 32695810
2022 miR-210-3p (upregulated by HIF-1α under hypoxia) downregulates EFNA3 expression and thereby enhances phosphorylation of the PI3K/AKT pathway to promote angiogenesis miRNA sequencing, luciferase reporter assay, Western blot for PI3K/AKT phosphorylation, HUVEC functional assays, in vivo calvarial bone defect model Acta biomaterialia Medium 35850484
2013 EFNA3 is a direct target of miR-210; miR-210 regulates EFNA3 mRNA and protein expression in MPNST cells, and EFNA3-mediated signaling promotes proliferation and invasion of malignant peripheral nerve sheath tumor cells Luciferase reporter assay, qRT-PCR, Western blot, cell viability/colony formation/invasion assays with miR-210 overexpression and inhibition Oncology research Medium 24512729
2022 lncRNA HOTTIP promotes EFNA3 transcription by recruiting the chromatin architectural protein CTCF to the EFNA3 promoter, and EFNA3 in turn drives airway inflammatory responses in asthma RNA pull-down, RNA immunoprecipitation, luciferase reporter assay, chromatin immunoprecipitation, in vivo OVA-asthma mouse model with EFNA3 knockdown American journal of translational research Medium 36628218
2022 hsa_circ_0007478 acts as a miR-765 sponge (competing endogenous RNA), upregulating EFNA3 expression; EFNA3 in turn regulates NLRP3 inflammasome activation, IL-1β levels, and lipid metabolism/foam cell formation in ox-LDL-stimulated macrophages microarray, qRT-PCR, siRNA knockdown, miR-765 mimic transfection, luciferase reporter assay for miR-765/EFNA3 interaction, NLRP3/IL-1β readouts Chemico-biological interactions Medium 36191606
2023 miR-423-5p targets and inhibits EFNA3 expression; hucMSC-derived extracellular vesicles deliver miR-423-5p to suppress EFNA3 in endothelial cells, thereby promoting HUVEC migration and angiogenesis; EFNA3 overexpression reverses these pro-angiogenic effects EV isolation and characterization, miR-423-5p mimic transfection, EFNA3 overexpression rescue, HUVEC migration/tube formation assays, in vivo rat MI model with capillary density measurement Postepy w kardiologii interwencyjnej Medium 36967852
2018 lncRNA EFNA3 acts as a sponge for miR-101a in PC-12 cells under hypoxia; sequestration of miR-101a by lncRNA EFNA3 de-represses ROCK2, which activates Wnt/β-catenin and suppresses JAK/STAT pathways to exert neuroprotective effects shRNA knockdown of lncRNA EFNA3, RNA pull-down, RNA immunoprecipitation, luciferase activity assay, qRT-PCR, Western blot for ROCK2, Wnt/β-catenin and JAK/STAT pathway components Journal of cellular biochemistry Medium 30125989
2024 hMAGEA2 binds to the EFNA3 promoter region and transcriptionally activates EFNA3; elevated EFNA3 drives Ras/Braf/MEK/Erk1/2 phosphorylation to promote prostate cancer proliferation, migration, and invasion Dual-luciferase reporter assay for EFNA3 promoter binding, Western blot for ERK1/2 phosphorylation, hMAGEA2 knockdown cell lines, CCK-8/colony formation/transwell assays Anticancer research Medium 38925815
2025 EphA3 physically interacts with EFNA3 (confirmed by co-immunoprecipitation); EphA3/EFNA3 reverse signaling promotes epithelial-to-mesenchymal transition (EMT) by activating ERK1/2 signaling, driving colorectal cancer metastasis Co-immunoprecipitation, EFNA3 knockdown/overexpression, transwell/wound healing/colony formation assays, subcutaneous and spleen injection tumor models in nude mice, Western blot for EMT and ERK1/2 markers Digestive diseases and sciences Medium 40928719
2025 NSUN5 (an m5C RNA methyltransferase) promotes m5C modification of EFNA3 mRNA, stabilizing EFNA3; elevated EFNA3 drives aerobic glycolysis in liver hepatocellular carcinoma cells, and EFNA3 overexpression rescues glycolysis suppressed by NSUN5 knockdown Methylated RNA immunoprecipitation, dual-luciferase reporter assay, NSUN5 knockdown, EFNA3 overexpression rescue, glycolysis measurements in vitro and xenograft tumor model in vivo BMC cancer Medium 40730949
2022 lncRNA LINC01270 acts as a competing endogenous RNA (ceRNA) for miR-326, thereby positively regulating EFNA3 expression; LINC01270/miR-326/EFNA3 axis promotes gastric cancer cell proliferation, migration, and invasion Luciferase reporter assay, RNA pull-down, qRT-PCR, Western blot, CCK-8/colony formation/transwell assays, rescue experiments with miR-326 inhibitor or EFNA3 overexpression Bioengineered Low 35345980
2023 EFNA3 is a direct target of miR-365; miR-365-mediated suppression of EFNA3 inhibits nucleus pulposus cell apoptosis, reduces MMP-13 expression, and preserves extracellular matrix (collagen II, aggrecan) in intervertebral disc degeneration Luciferase reporter assay, miR-365 mimic/inhibitor transfection, immunofluorescence, flow cytometry apoptosis assay, in vivo rat IDD model with NP cell injection Journal of cellular and molecular medicine Medium 38009813
2024 Recombinant EFNA3 (rEFNA3) administered topically promotes vaginal epithelial expression of desmosomal cadherins DSG1 and DSC1 in a biphasic dose-dependent manner and partially restores vaginal epithelial barrier function lost after DMPA (progestin) treatment Topical administration of recombinant EFNA3 in mice, Western blot/gene expression for DSG1/DSC1, epithelial barrier function assay, HSV-2 infection morbidity/mortality challenge bioRxiv (preprint)preprint Low bio_10.1101_2024.10.29.620915
2024 EFNA3, produced by basal cells of the mammary epithelium, targets luminal cells and enhances oxidative phosphorylation (OXPHOS) to provide energy that promotes collective epithelial migration and branching morphogenesis; inhibition of EFNA3 slows breast cancer metastasis Cell-type-specific EFNA3 expression analysis, OXPHOS measurements, in vivo mammary gland branching morphogenesis assay, EFNA3 inhibition in cancer metastasis models bioRxiv (preprint)preprint Low bio_10.1101_2024.10.18.619009
2026 EFNA3 activates the PI3K/AKT/mTOR signaling pathway, suppresses autophagy, and promotes breast cancer cell proliferation, EMT, and metastasis; EFNA3 knockdown induces autophagy and inhibits tumor growth in xenograft models EFNA3 knockdown/overexpression, Western blot for PI3K/AKT/mTOR phosphorylation, LC3 staining, transmission electron microscopy for autophagy, xenograft mouse model The international journal of biochemistry & cell biology Medium 41763291
1996 EFNA3 (LERK-3/EPLG3) is a GPI-anchored membrane protein that functions as a ligand for Eph-related receptor tyrosine kinases (hek and elk); its gene maps to human chromosome 1q21-q22 and mouse chromosome 3 Southern hybridization of human×rodent somatic cell hybrids, fluorescence in situ hybridization, Southern blot of interspecific backcross mice, structural characterization (GPI anchor vs transmembrane) Genomics High 8660976

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 78 35850484
2020 OSCC Exosomes Regulate miR-210-3p Targeting EFNA3 to Promote Oral Cancer Angiogenesis through the PI3K/AKT Pathway. BioMed research international 78 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 19 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 14 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
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 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 8 36967852
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 6 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
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 EphA3/EFNA3 Reverse Signalling Promotes Epithelial-to-Mesenchymal Transition via ERK Pathway to Facilitate Colorectal Cancer Metastasis. Digestive diseases and sciences 0 40928719
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