Affinage

EPHB6

Ephrin type-B receptor 6 · UniProt O15197

Length
1021 aa
Mass
110.7 kDa
Annotated
2026-06-09
63 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EPHB6 is an intrinsically kinase-deficient (pseudokinase) Eph receptor that binds ephrin-B2 as its high-affinity ligand and signals not through its own catalytic activity but by being transphosphorylated by catalytically active partners and by acting as a scaffold for adaptor recruitment (PMID:10648835, PMID:11713248). Its juxtamembrane tyrosines are substrates for active EphB-family and Src-family kinases—EphB1, EphB4, and the constitutively associated Fyn—and once phosphorylated they recruit SH2-domain proteins including Abl, Src, and Vav3, while constitutive recruitment of c-Cbl and Hsp90 occurs through the cytoplasmic region (PMID:11713248, PMID:15955811, PMID:34431498, PMID:20086179, PMID:25152371). Structurally, the extracellular domain adopts an architecture resembling unliganded A-class Eph receptors and the intracellular pseudokinase and SAM modules are highly flexible, retaining residual ATP binding despite catalytic deficiency (PMID:33770085, PMID:34431498). In T cells EPHB6 partitions to TCR-containing lipid rafts and is required for full proximal TCR signaling (ZAP-70, LAT, PLCγ1-SLP-76, MAPK), exerting ligand- and concentration-dependent modulation of Rac1/JNK, IL-2 secretion, proliferation, and apoptosis (PMID:15599401, PMID:12393850, PMID:12517763). Through ephrin-B reverse signaling and adaptor coupling, EPHB6 controls vascular smooth muscle contractility via RhoA and GRIP1 and governs adrenal chromaffin-cell catecholamine biosynthesis (RAC1-MKK7-JNK-c-Jun/AP1-EGR1 driving tyrosine hydroxylase) and testosterone-dependent secretion (BKCa-regulated Ca2+ influx and RHOA/FYN-ABL-MICAL-1-dependent cortical F-actin disassembly) (PMID:22223652, PMID:30824540, PMID:29339804, PMID:32321761). In cancer, EPHB6 generally suppresses invasiveness—by transphosphorylation-dependent c-Cbl/Abl signaling, by sequestering and restraining kinase-active oncogenic Eph receptors such as EphA2, and by trans co-clustering with ephrin-B1 to stabilize cell-cell adhesion—but also drives context-specific pro-tumorigenic outputs through GRB2-RAS-ERK-OCT4, ERK-DRP1 mitochondrial fission, EGFR crosstalk, and a TFEB-lysosomal survival program (PMID:20086179, PMID:21737611, PMID:25239188, PMID:38627519, PMID:29700392, PMID:27788485, PMID:37392382, PMID:33802447). Receptor levels are set post-translationally by ligand-induced clathrin/Rab5-dependent lysosomal degradation following Hsp90 dissociation and by SIAH2-mediated K48-linked ubiquitination (PMID:25152371, PMID:42036676).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2000 High

    Establishing which ephrin engages EPHB6 was the prerequisite for any signaling model; the work defined ephrin-B2 as its specific high-affinity ligand.

    Evidence EphB6-Fc binding to ephrin-transfected COS and Reh cells with PIPLC and saturation controls

    PMID:10648835

    Open questions at the time
    • Did not address downstream signaling consequences of binding
    • In vitro fusion-protein binding may not reflect full-length receptor avidity
  2. 2001 High

    Because EPHB6 lacks intrinsic kinase activity, how it is activated was unresolved; transphosphorylation by catalytically active EphB1 within a stable heterocomplex, plus constitutive c-Cbl binding, defined the pseudokinase signaling logic.

    Evidence Co-IP with catalytically active/inactive EphB1, ligand stimulation, kinase assays

    PMID:11713248

    Open questions at the time
    • Which juxtamembrane tyrosines are phosphorylated not mapped here
    • Functional consequence of Cbl binding not determined
  3. 2001 Medium

    Whether EPHB6 has cell-autonomous immune function was unknown; cross-linking in T cells showed it couples to Cbl/SHP-1 dynamics and controls proliferation and apoptosis.

    Evidence Anti-EphB6/anti-CD3 co-cross-linking, Co-IP, apoptosis assays in Jurkat cells

    PMID:11466354

    Open questions at the time
    • Single cell line and single study
    • Mechanism linking Cbl dephosphorylation to apoptosis not dissected
  4. 2002 Medium

    The directionality of EPHB6's T-cell role was clarified by showing it co-localizes with the TCR at membrane rafts and co-stimulates proliferation via p38, and by confirming ephrin-B2 as its unique thymocyte ligand.

    Evidence Confocal co-localization, cytokine/proliferation assays, p38 assays; ephrin-Fc binding on KO thymocytes

    PMID:12379224 PMID:12393850

    Open questions at the time
    • Adaptor linkage between EPHB6 and p38 not defined
    • Co-stimulation context requires suboptimal TCR signal
  5. 2003 High

    To resolve which signaling arm EPHB6 modulates in T cells, ligand stimulation was shown to selectively inhibit TCR-induced Rac1-JNK (not MAPK) and IL-2/CD25, with dominant-negative rescue.

    Evidence WT and dominant-negative overexpression, Rac1 PAK pull-down, JNK assay, IL-2 ELISA, flow cytometry

    PMID:12517763

    Open questions at the time
    • Direct biochemical link from EPHB6 to Rac1 regulation not shown
    • Overexpression context
  6. 2004 High

    Genetic loss-of-function defined EPHB6 as required (not merely modulatory) for full proximal TCR signaling, anchoring its physiological immune role.

    Evidence EphB6-KO mice, raft fractionation, ZAP-70/LAT/PLCγ1-SLP-76/MAPK readouts, in vivo T-cell assays

    PMID:15599401

    Open questions at the time
    • Molecular mechanism of how a kinase-dead receptor enhances ZAP-70/LAT not resolved
  7. 2005 High

    The dual positive/negative behavior of EPHB6 was explained by a concentration-dependent switch in which constitutive Fyn association and Src-family-driven tyrosine phosphorylation convert adhesion-promoting into repulsive signaling.

    Evidence Adhesion/migration assays at varying ligand dose, cytoplasmic deletion mutants, Fyn Co-IP, SFK inhibitors

    PMID:15955811

    Open questions at the time
    • Identity of phosphosites driving the switch not mapped
    • Downstream effectors of repulsion not defined
  8. 2009 Medium

    Whether EPHB6 engages ERK in epithelial cancers and whether that drives transcription was tested, showing ERK phosphorylation uncoupled from Elk-1 activation.

    Evidence Overexpression/siRNA in A549 cells, ERK immunoblot, Elk-1 reporter

    PMID:19513565

    Open questions at the time
    • Mechanism of ERK-Elk1 uncoupling unexplained
    • Single cell line
  9. 2010 High

    The mechanism of EPHB6's tumor-suppressive activity was placed downstream of EphB4 transphosphorylation, requiring c-Cbl-dependent Abl phosphorylation to inhibit invasiveness.

    Evidence EPHB6 restoration in breast cancer cells, c-Cbl Co-IP, Cbl siRNA rescue, Abl phosphorylation and invasion assays

    PMID:20086179

    Open questions at the time
    • Quantitative balance of EphB6/EphB4 in vivo not established
  10. 2011 Medium

    A sequestration model for tumor suppression was supported by demonstrating EPHB6 heterointeractions with EphB2 and, unprecedentedly, with the A-class EphA2.

    Evidence Co-IP across breast carcinoma cell lines

    PMID:21737611

    Open questions at the time
    • Single Co-IP per pair without reciprocal/functional validation
    • Stoichiometry of sequestration unknown
  11. 2014 Medium

    Receptor turnover and the EPHB6-EphA2 axis were mechanistically defined: ligand-induced Hsp90 dissociation triggers clathrin/Rab5 lysosomal degradation, and EPHB6 restrains EphA2 S897 phosphorylation/Ephexin4-RhoG to suppress anoikis resistance.

    Evidence Dominant-negative Rab5, clathrin/lysosome inhibitors, Hsp90 Co-IP and geldanamycin; EphA2 phospho/RhoG/anoikis assays

    PMID:25152371 PMID:25239188

    Open questions at the time
    • E3 ligase for lysosomal route not identified here
    • Hsp90 binding site on EPHB6 unmapped
  12. 2012 High

    Beyond immunity, EPHB6 was assigned a cardiovascular role: KO arteries show heightened contractility via RhoA/myosin light chain, with ephrin-B reverse signaling acting through GRIP1.

    Evidence EphB6-KO mice, ex vivo contractility, RhoA assay, MLC phospho-immunoblot, cross-linking, BP/catecholamine measurement

    PMID:22223652

    Open questions at the time
    • Sex/testosterone dependence first hinted but not mechanistically resolved here
  13. 2018 High

    EPHB6's adrenal function was opened by linking it to chromaffin-cell excitability: KO augments BKCa currents and reduces ACh-triggered Ca2+ influx in a testosterone-dependent manner.

    Evidence Patch-clamp, Ca2+ imaging, BKCa blockade, KO mice with castration controls

    PMID:29339804

    Open questions at the time
    • How EPHB6 regulates BKCa channels molecularly not defined
    • Mechanism of testosterone dependence unresolved
  14. 2019 High

    The biosynthetic arm of catecholamine control was defined: EPHB6 reverse signaling through ephrin-B1 drives tyrosine hydroxylase transcription via RAC1-MKK7-JNK-c-Jun/AP1-EGR1.

    Evidence KO mice, RT-qPCR, immunoblot, microarray, pathway inhibitors, HPLC catecholamines

    PMID:30824540

    Open questions at the time
    • Direct transcription factor occupancy at TH promoter not shown
  15. 2020 High

    The secretory arm was completed by showing EPHB6-to-ephrin-B1 reverse signaling regulates exocytosis through RHOA and FYN-ABL-MICAL-1-dependent cortical F-actin disassembly, with a defined 7-residue ephrin-B1 tail motif.

    Evidence Amperometry, F-actin quantification, ephrin-B1 tail deletion mutants, pathway inhibition, KO mice

    PMID:32321761

    Open questions at the time
    • How testosterone gates this pathway not molecularly resolved
  16. 2016 Medium

    A pro-apoptotic cancer output was identified whereby EPHB6 activates ERK-DRP1 to fragment mitochondria, sensitizing TNBC cells to DR5-mediated apoptosis.

    Evidence Mitochondrial imaging, ERK/DRP1 phospho assays, DRP1 inhibitor/knockdown, DR5 agonist apoptosis

    PMID:27788485

    Open questions at the time
    • Link from EPHB6 to ERK activation upstream not biochemically defined
    • Single lab
  17. 2018 Medium

    A context-dependent pro-tumorigenic function was shown via GRB2 recruitment activating RAS-ERK-OCT4 to expand tumor-initiating cells, revealing EPHB6's dual cancer roles.

    Evidence GRB2 Co-IP, ERK inhibitor and OCT4 knockdown, xenografts, TIC flow cytometry

    PMID:29700392

    Open questions at the time
    • Reconciliation with tumor-suppressive roles context-dependent and unresolved
  18. 2017 Medium

    Transcriptional regulation of EPHB6 in prostate cancer was defined: AR binds an ARE to repress EPHB6, derepressing JNK-MMP9-driven invasion.

    Evidence ChIP/ARE binding, promoter reporter, JNK phospho, JNK inhibitor, invasion assays

    PMID:28826721

    Open questions at the time
    • Single lab; direct EPHB6-to-JNK biochemical link not shown
  19. 2019 Medium

    A drug-resistance mechanism was mapped: mutated EPHB6 engages EphA2 to drive JNK-CDH11 and RhoA/FAK, conferring adhesion-mediated paclitaxel resistance reversible by targeting EphA2 or CDH11.

    Evidence EphA2 Co-IP, CDH11/JNK/RhoA-FAK assays, inhibitors, resistance assays

    PMID:31160603

    Open questions at the time
    • Specific EPHB6 mutations and their structural effect not resolved
    • Single lab
  20. 2020 Medium

    An upstream regulator-EPHB6-effector axis in lung cancer was defined whereby CLDN1 enhances EPHB6 to suppress ERK1/2-SLUG, repressing metastasis and stemness.

    Evidence IP, migration/sphere/xenograft assays, siRNA knockdown

    PMID:32754286

    Open questions at the time
    • How CLDN1 enhances EPHB6 activation mechanistically unclear
  21. 2021 High

    Structural understanding of the kinase-dead receptor was advanced: the ECD resembles unliganded A-class Ephs, and the flexible intracellular JM/pseudokinase/SAM region presents EphB4-phosphorylated tyrosines that bind Abl/Src/Vav3 SH2 domains, with residual ATP binding.

    Evidence X-ray crystallography of ECD; SAXS, XL-MS, in vitro EphB4 kinase, SH2 pull-downs, ATP binding

    PMID:33770085 PMID:34431498

    Open questions at the time
    • Full-length receptor structure absent
    • Functional role of residual ATP binding in cells untested
  22. 2021 Medium

    A pro-survival role in metastatic dormancy was identified through EPHB6 activation of the TFEB-lysosomal axis in disseminated dormant cancer cells.

    Evidence Lung organotypic co-culture, in vivo dissemination, TFEB reporter, lysosome staining, knockdown, xenograft

    PMID:33802447

    Open questions at the time
    • Signaling link from EPHB6 to TFEB not biochemically defined
  23. 2023 Medium

    Unbiased screening extended EPHB6 partners to EGFR, showing crosstalk that enhances cancer-cell proliferation and tumor development; separately, EPHB6 deficiency was shown to promote colorectal tumor growth via intestinal-neuron GABA/SNAP25.

    Evidence Genetic screen + BioID + machine learning with validation; KO xenograft, GABA/SNAP25 assays, botulinum toxin rescue

    PMID:37294054 PMID:37392382

    Open questions at the time
    • Direct EPHB6-EGFR biochemical interface not defined
    • Neuronal-tumor axis from single lab
  24. 2023 Medium

    A developmental neuronal role was shown in which EPHB6 and ephrin-B2 overexpression each cause cortical soma clumping that mutually cancels, indicating domain-specific cis/trans interaction controlling neuronal spacing.

    Evidence In utero electroporation, cortical neuron imaging, domain-specific interaction analysis

    PMID:37149633

    Open questions at the time
    • Loss-of-function neuronal phenotype not shown
    • Downstream effectors unmapped
  25. 2024 High

    High-resolution imaging defined the adhesive output: EPHB6 trans co-clustering with ephrin-B1 forms endocytosis-resistant clusters and double-membrane tubules that stabilize cell-cell contacts and reduce invasion.

    Evidence Lattice light-sheet, 3D-SIM, cryo-electron tomography, endocytosis and invasion assays

    PMID:38627519

    Open questions at the time
    • Molecular composition of tubular structures not fully resolved
  26. 2026 Medium

    Post-translational control was extended by showing SIAH2 drives K48-ubiquitination and proteasomal degradation of EPHB6, derepressing RHOF-driven filopodia and invasion in hepatocellular carcinoma.

    Evidence SIAH2-EPHB6 Co-IP, K48-linkage ubiquitination assay, knockdown/overexpression, RHOF and filopodia/invasion assays

    PMID:42036676

    Open questions at the time
    • SIAH2 recognition motif on EPHB6 not mapped
    • Single lab, single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EPHB6's many context-specific outputs (tumor suppression vs promotion, immune, vascular, adrenal, neuronal) are selected by partner availability, phosphosite occupancy, and tissue context remains unresolved.
  • No unified model reconciling opposing cancer roles
  • Endogenous heterocomplex stoichiometry across tissues unknown
  • Full-length receptor signaling structure undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0098772 molecular function regulator activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 2 GO:0005768 endosome 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 2
Partners
CBLEFNB1EFNB2EPHA2EPHB1EPHB4FYNGRB2

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 EphB6, despite lacking intrinsic kinase activity, undergoes ligand-induced tyrosine phosphorylation via transphosphorylation by the catalytically active EphB1 receptor. EphB1 and EphB6 form a stable heterocomplex, and EphB1-induced EphB6 phosphorylation is ligand-dependent and requires EphB1 catalytic activity. Additionally, the proto-oncogene c-Cbl was identified as an EphB6-binding protein; EphB6-Cbl association is constitutive and requires a functional phosphotyrosine binding domain on Cbl. Co-immunoprecipitation, overexpression of catalytically active/inactive EphB1, ligand stimulation with ephrin-B1, kinase assays The Journal of biological chemistry High 11713248
2001 Cross-linking of EphB6 in Jurkat T cells triggers general protein tyrosine phosphorylation and associates with Cbl. EphB6 cross-linking results in Cbl dephosphorylation and dissociation of Cbl from SHP-1, leading to altered lymphokine secretion, proliferation inhibition, and Fas-mediated apoptosis. Co-cross-linking with anti-EphB6 antibody and anti-CD3, Co-immunoprecipitation, apoptosis assays Journal of immunology Medium 11466354
2002 EphB6 crosslinking by anti-EphB6 mAb or ephrin-B2 in the presence of suboptimal TCR stimulation co-stimulates T cell proliferation and cytokine secretion. Within two minutes of anti-CD3/anti-CD28 stimulation, EphB6 aggregates and co-localizes with TCR at membrane rafts, and this is followed by p38 MAPK activation. Anti-EphB6 crosslinking, confocal microscopy for co-localization with TCR, cytokine ELISA, proliferation assays, p38 MAPK activation assays The Journal of clinical investigation Medium 12393850
2003 EphB6 overexpression in Jurkat T cells followed by ephrin-B1 stimulation selectively inhibits TCR-mediated JNK activation but not the MAPK pathway. The mechanism involves suppression of TCR-induced Rac1 GTPase activation upstream of JNK. EphB6 also blocks anti-CD3-induced IL-2 secretion and CD25 expression in a ligand-dependent manner. Dominant-negative EphB6 reverses these inhibitory effects. In murine thymocytes, ephrin-B1 stimulation inhibits TCR-mediated apoptosis and CD25 upregulation. Overexpression of wild-type and dominant-negative EphB6, Rac1 activation assay (GST-PAK pull-down), JNK kinase assay, IL-2 ELISA, flow cytometry for CD25 The Journal of biological chemistry High 12517763
2004 EphB6 migrates to aggregated TCRs and lipid rafts after TCR activation in T cells. In EphB6-deficient mice, ZAP-70 activation, LAT phosphorylation, PLCγ1 association with SLP-76, and p44/42 MAPK activation are diminished upon TCR stimulation, demonstrating EphB6 is required for full TCR downstream signaling. EphB6 knockout mice, biochemical fractionation to isolate rafts, immunoblotting for ZAP-70, LAT, PLCγ1/SLP-76 co-IP, MAPK activation assays, in vivo T cell functional assays The Journal of clinical investigation High 15599401
2000 Ephrin-B2 is a high-affinity ligand for EphB6. EphB6-Fc fusion protein binds ephrin-B2 but not ephrin-B1 on transfected COS cells in a saturable manner. The ligand identified on Reh pro-B cells is a transmembrane ephrin (not GPI-anchored, as PIPLC treatment did not abrogate binding). EphB6-Fc fusion protein binding assay, COS cell transfection with ephrin-B1 or ephrin-B2, phosphatidylinositol-specific phospholipase C treatment, saturation binding analysis FEBS letters High 10648835
2002 Ephrin-B2 is the unique ligand for EphB6 among eight known ephrins, as demonstrated by differential binding of ephrin-Fc proteins to EphB6-deficient versus wild-type thymocytes. EphB6 is the dominant ephrin-B2-binding receptor on adult thymocytes. EphB6 knockout mice, ephrin-Fc binding assays on thymocytes Biochemical and biophysical research communications Medium 12379224
2005 EphB6 exerts biphasic effects on cell adhesion and migration: low concentrations of ephrin-B2 promote adhesion and migration, while high concentrations induce repulsion and inhibit migration. A truncated EphB6 lacking the cytoplasmic domain shows only positive (monophasic) effects, indicating the cytoplasmic domain mediates negative effects. EphB6 is constitutively associated with the Src family kinase Fyn, and high ephrin-B2 concentrations induce EphB6 tyrosine phosphorylation through Src family kinase activity as the molecular switch. Cell adhesion and migration assays with varying ligand concentrations, cytoplasmic domain deletion mutants, co-immunoprecipitation with Fyn, Src family kinase inhibitors, tyrosine phosphorylation assays The Journal of biological chemistry High 15955811
2010 EphB6 suppresses breast cancer cell invasiveness through a mechanism requiring EphB4-mediated transphosphorylation of EphB6, followed by EphB6-c-Cbl interaction and phosphorylation of the Abl kinase. Cbl silencing suppresses Abl phosphorylation, cell adhesion, and morphological changes, and blocks EphB6's ability to inhibit invasiveness. EphB4 also acts in an EphB6-independent manner to enhance invasiveness, suggesting cancer invasiveness is defined by the balance in the EphB6-EphB4 system. Restoration of EphB6 expression in invasive breast cancer cells, Co-immunoprecipitation of EphB6 with c-Cbl, siRNA knockdown of Cbl, Abl phosphorylation assays, invasion assays Cancer research High 20086179
2011 EPHB6 interacts with EPHB2 and with EPHA2 (the first demonstrated A-type/B-type Eph receptor interaction), but does not interact with another kinase-deficient receptor EPHA10. The tumor-invasiveness-suppressing activity of EPHB6 is mediated partly by sequestering kinase-sufficient oncogenic EPH receptors. Co-immunoprecipitation in mammalian breast carcinoma cell lines Cancer genomics & proteomics Medium 21737611
2014 EphB6 interacts with EphA2 and suppresses EphA2-mediated anoikis resistance in MCF7 breast cancer cells by decreasing serine 897 phosphorylation of EphA2 and suppressing EphA2-Ephexin4 interaction and RhoG activation. Knockdown of EphB6 promotes anoikis resistance. Co-immunoprecipitation, phosphorylation assays, siRNA knockdown of EphB6, RhoG activation assay, anoikis assay Cellular signalling Medium 25239188
2012 EPHB6 and its ephrin-B ligands are expressed on vascular smooth muscle cells (VSMC). In castrated male Ephb6-KO mice, small arteries show increased contractility, RhoA activation, and constitutive myosin light chain phosphorylation ex vivo. Cross-linking ephrin-Bs (reverse signaling) but not EphB6 (forward signaling) reduces VSMC contractions, mediated by the adaptor protein GRIP1. Male Ephb6-KO mice show decreased 24-hour urine catecholamines as a compensatory mechanism. EphB6 knockout mice, ex vivo arterial contractility assays, RhoA activation assay, myosin light chain phosphorylation immunoblot, cross-linking assays, blood pressure measurement, catecholamine measurement The Journal of biological chemistry High 22223652
2019 EPHB6 controls catecholamine biosynthesis in adrenal gland chromaffin cells (AGCCs) by upregulating tyrosine hydroxylase transcription. Ephb6-KO male mice have reduced epinephrine content due to decreased tyrosine hydroxylase. The signaling pathway from EPHB6 to tyrosine hydroxylase involves RAC1, MKK7, JNK, c-Jun, AP1, and EGR1. This effect operates via reverse signaling through ephrin-B1. ERK1/2, p38 MAPK, and ELK1 signaling were not affected by EPHB6 deletion. EphB6 knockout mice, RT-qPCR, immunoblotting, gene microarray, signaling pathway inhibitors, HPLC catecholamine measurement The Journal of biological chemistry High 30824540
2018 In male Ephb6-KO adrenal gland chromaffin cells, acetylcholine-triggered Ca2+ influx is reduced due to augmented large conductance calcium-activated potassium (BKCa) channel currents in a testosterone-dependent manner. Blocking BKCa channels in KO cells corrects the reduced Ca2+ influx. This phenotype depends on the non-genomic effect of testosterone and is absent in female or castrated KO mice. Patch-clamp electrophysiology, Ca2+ imaging, BKCa channel pharmacological blockade, EphB6 knockout mice, castration experiments Scientific reports High 29339804
2020 In male Ephb6-KO adrenal gland chromaffin cells, catecholamine secretion via exocytosis is compromised and is accompanied by reduced cortical F-actin disassembly. Reverse signaling from EPHB6 to ephrin-B1 and a 7-amino acid segment in the EFNB1 intracellular tail are essential for this regulation. Downstream, RHOA and FYN-ABL-MICAL-1 pathways mediate signaling from EFNB1 to defective F-actin disassembly. This phenotype is testosterone-dependent and absent in female KO mice. Amperometry recordings of catecholamine secretion, F-actin staining/quantification, EphB6 knockout mice, ephrin-B1 tail deletion mutants, pathway inhibition assays The Journal of biological chemistry High 32321761
2018 EPHB6 interacts with the GRB2 adapter protein and promotes expansion of tumor-initiating cells (TICs) via activation of the RAS-ERK pathway, elevating OCT4 expression. Suppression of ERK or OCT4 blocks EPHB6-induced pro-proliferative responses. EPHB6 also partially suppresses epithelial-mesenchymal transition in TNBC cells. Co-immunoprecipitation of EPHB6 with GRB2, ERK pathway inhibitor experiments, OCT4 knockdown, xenograft models, flow cytometry for TIC populations Oncogene Medium 29700392
2016 EPHB6 induces mitochondrial network fragmentation in triple-negative breast cancer cells by activating the ERK-DRP1 pathway, increasing organelle fission. This mitochondrial fragmentation renders cancer cells more susceptible to DR5-mediated apoptosis. DRP1 activity is essential for the EPHB6-mediated pro-apoptotic response. Mitochondrial morphology imaging, ERK activation assays, DRP1 phosphorylation assays, DRP1 inhibitor/knockdown experiments, DR5 agonist apoptosis assays Oncotarget Medium 27788485
2014 Ligand-induced (ephrin-B2) downregulation of EphB6 occurs through internalization via clathrin-coated pits followed by lysosomal degradation, dependent on Rab5 GTPase activity. EphB6 interacts constitutively with the Hsp90 chaperone, and ligand-induced downregulation is preceded by rapid EphB6-Hsp90 dissociation. Hsp90 inhibition alone induces EphB6 degradation, mimicking ligand-induced downregulation. Dominant-negative Rab5 mutant expression, clathrin inhibitors, lysosomal pathway inhibitors, Co-immunoprecipitation of EphB6 with Hsp90, Hsp90 inhibitor (geldanamycin) treatment, receptor degradation assays Cellular signalling Medium 25152371
2021 The intracellular regions of EphB6 comprising the juxtamembrane (JM) region, pseudokinase, and SAM domains display high flexibility in solution and a propensity for inter-domain interactions. Tyrosine residues in the JM region of EphB6 are substrates for EphB4 kinase and, when phosphorylated, bind SH2 domains of Abl, Src, and Vav3. EphB6 and EphA10 pseudokinase domains can bind ATP and ATP-competitive small molecules. Small-angle X-ray scattering (SAXS), cross-linking mass spectrometry, in vitro EphB4 kinase assay, SH2 domain pull-down assays, ATP binding assays The Biochemical journal High 34431498
2021 Crystal structure of the EphB6 extracellular domain (ECD) was determined by X-ray crystallography, revealing the overall architecture including ligand-binding domain (LBD) and fibronectin III domain (FN3). EphB6-LBD/FN3 interactions are similar to those observed in unliganded A-class Eph receptors, suggesting general importance. Unique structural features of EphB6 likely reflect its requirement for co-receptors due to lack of intrinsic kinase activity. X-ray crystallography of EphB6-ECD PloS one High 33770085
2023 EPHB6 modulates EGFR signaling to enhance proliferation of cancer cells and tumor development, as identified by genetic screening and BioID proteomics integrated with machine learning. Further experiments confirmed the EPHB6-EGFR crosstalk. Genome-wide genetic interaction screen, BioID proximity proteomics, machine learning integration, functional validation experiments Cell reports Medium 37392382
2009 Expression of EPHB6 in A549 lung adenocarcinoma cells leads to phosphorylation of ERK (MAP kinase). siRNA-based knockdown of EPHB6 reverses ERK phosphorylation. However, EPHB6-induced ERK phosphorylation is uncoupled from activation of the Elk-1 transcriptional factor. EPHB6 overexpression, siRNA knockdown, ERK phosphorylation immunoblotting, Elk-1 reporter assays International journal of oncology Medium 19513565
2020 CLDN1 upregulates cellular EPHB6 levels and enhances its activation, resulting in suppression of ERK1/2 signaling and downstream inhibition of SLUG expression, forming a CLDN1-EPHB6-ERK1/2-SLUG feedback axis that represses metastasis, drug resistance, and cancer stemness in lung adenocarcinoma. Immunoblotting, immunoprecipitation, migration assays, sphere assay, xenograft experiments, siRNA knockdown Theranostics Medium 32754286
2019 EPHB6 mutation-induced paclitaxel resistance is mediated by interaction with EPHA2, which promotes JNK-mediated cadherin 11 (CDH11) expression. EPHB6-mutated cells acquire cell adhesion-mediated drug resistance via CDH11 expression and RhoA/FAK activation. Targeted inhibition of EPHA2 or CDH11 reverses paclitaxel resistance. Co-immunoprecipitation of EPHB6 with EPHA2, CDH11 expression assays, JNK phosphorylation assays, RhoA/FAK activation assays, pharmacological inhibitor experiments, drug resistance assays Experimental & molecular medicine Medium 31160603
2024 EphB6 interacts with ephrin-B1 in trans on neighboring cells, leading to formation of large co-clusters at the plasma membrane. These co-clusters show decreased propensity for endocytosis. Co-clustering promotes formation of double-membrane tubular structures between cells, stabilizes cell-cell adhesion, and reduces invasive behavior of cancer cells. Lattice light-sheet microscopy, 3D structured illumination microscopy, cryo-electron tomography, endocytosis assays, cell invasion assays Communications biology High 38627519
2023 EphB6 deficiency in mice promotes tumor growth in a colorectal cancer xenograft model by increasing GABA in the tumor microenvironment through intestinal neurons. The mechanism involves increased expression of synaptosomal-associated protein 25 (SNAP25) in the intestinal myenteric plexus, mediating GABA release. Botulinum toxin A injection into the rectum of EphB6-deficient mice eliminated the pro-tumorigenic effect, confirming the neuronal dependency. EphB6-deficient mouse xenograft model, GABA measurement, SNAP25 immunoblotting, botulinum toxin A neuronal inhibition, gut microbiota controls Carcinogenesis Medium 37294054
2021 EphB6 promotes survival of disseminated dormant cancer cells (DDCCs) in the lung through activation of the TFEB-lysosomal axis. Direct co-culture of DDCCs with lung epithelial cells induces EphB6 expression and lysosomal accumulation. EphB6 contributes to TFEB transcriptional activity and lysosome formation. EphB6 signaling also promotes proliferation of surrounding lung parenchymal cells in vivo. Lung organotypic co-culture system, in vivo dissemination assays, TFEB reporter assays, lysosome staining, EphB6 knockdown, xenograft models Cancers Medium 33802447
2026 SIAH2 promotes K48-linked polyubiquitination and proteasomal degradation of EPHB6 in hepatocellular carcinoma cells. Loss of EPHB6 through SIAH2-mediated degradation promotes filopodia formation and cell invasion/migration via upregulation of RHOF. Co-immunoprecipitation of SIAH2 with EPHB6, ubiquitination assays (K48-linkage specific), EPHB6 knockdown/overexpression, RHOF expression assays, filopodia quantification, invasion/migration assays Cell & bioscience Medium 42036676
2024 EPHB6 interacts with CBX7 in cervical cancer C33A cells, and EPHB6 inhibits cell proliferation, invasion, migration, and cell cycle acceleration by binding to CBX7. Co-immunoprecipitation, HDOCK molecular docking prediction, functional assays (CCK-8, EdU, wound healing, transwell), flow cytometry for cell cycle Cell biochemistry and biophysics Low 39322790
2017 Enzalutamide-mediated androgen receptor (AR) activation binds to an androgen-response-element (ARE) on the EPHB6 promoter to decrease EPHB6 expression, which then activates JNK phosphorylation and increases MMP9 expression to promote CRPC cell invasion. JNK inhibitor SP600125 blocks Enzalutamide-increased CRPC cell invasion. ARE binding assay/ChIP, EPHB6 promoter reporter assay, JNK phosphorylation immunoblot, JNK inhibitor treatment, invasion assays Cancer letters Medium 28826721
2023 Overexpression of EphB6 via in utero electroporation results in clumping of cortical neurons (soma spacing defect), as does overexpression of ephrin-B2. When both EphB6 and ephrin-B2 are co-overexpressed in cortical neurons, the soma clumping phenotypes disappear, demonstrating mutual inhibition requiring interaction of their specific domains. In utero electroporation, cortical neuron imaging, domain-specific interaction analysis Cell death & disease Medium 37149633

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice. Microbiome 113 32819434
2000 Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma. Proceedings of the National Academy of Sciences of the United States of America 86 10984508
2001 The kinase-null EphB6 receptor undergoes transphosphorylation in a complex with EphB1. The Journal of biological chemistry 83 11713248
2004 EphB6-null mutation results in compromised T cell function. The Journal of clinical investigation 79 15599401
2010 The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells. Cancer research 75 20086179
2010 The EPHB6 receptor tyrosine kinase is a metastasis suppressor that is frequently silenced by promoter DNA hypermethylation in non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 75 20371680
2003 Loss of EphB6 expression in metastatic melanoma. International journal of oncology 75 14612926
1999 High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas. Clinical cancer research : an official journal of the American Association for Cancer Research 74 10389937
2002 EphB6 crosslinking results in costimulation of T cells. The Journal of clinical investigation 66 12393850
2005 Biphasic functions of the kinase-defective Ephb6 receptor in cell adhesion and migration. The Journal of biological chemistry 64 15955811
2009 EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells. Oncogene 61 19234485
2003 The EphB6 receptor inhibits JNK activation in T lymphocytes and modulates T cell receptor-mediated responses. The Journal of biological chemistry 57 12517763
2001 Cross-linking of EphB6 resulting in signal transduction and apoptosis in Jurkat cells. Journal of immunology (Baltimore, Md. : 1950) 56 11466354
2000 Ephrin-B2 is a candidate ligand for the Eph receptor, EphB6. FEBS letters 38 10648835
2012 Receptor tyrosine kinase Ephb6 regulates vascular smooth muscle contractility and modulates blood pressure in concert with sex hormones. The Journal of biological chemistry 37 22223652
2011 A paradigm shift in EPH receptor interaction: biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines. Cancer genomics & proteomics 37 21737611
2011 EphB6 receptor modulates micro RNA profile of breast carcinoma cells. PloS one 37 21811619
2018 EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours. Oncogene 36 29700392
2005 Transcriptional silencing of EphB6 receptor tyrosine kinase in invasive breast carcinoma cells and detection of methylated promoter by methylation specific PCR. Biochemical and biophysical research communications 36 16364251
2019 LncRNA DGCR5 regulates the non-small cell lung cancer cell growth, migration, and invasion through regulating miR-211-5p/EPHB6 axis. BioFactors (Oxford, England) 32 31241800
2014 Dynamic interactions between cancer cells and the embryonic microenvironment regulate cell invasion and reveal EphB6 as a metastasis suppressor. Molecular cancer research : MCR 32 24836890
2014 EphB6 promotes anoikis by modulating EphA2 signaling. Cellular signalling 32 25239188
2000 T-cell-specific expression of kinase-defective Eph-family receptor protein, EphB6 in normal as well as transformed hematopoietic cells. Growth factors (Chur, Switzerland) 28 10831073
2020 DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. Theranostics 26 32754286
2016 EphB6 overexpression and Apc mutation together promote colorectal cancer. Oncotarget 26 27145271
2002 Developmental expression of EphB6 in the thymus: lessons from EphB6 knockout mice. Biochemical and biophysical research communications 26 12379224
2017 Androgen-deprivation therapy with enzalutamide enhances prostate cancer metastasis via decreasing the EPHB6 suppressor expression. Cancer letters 24 28826721
2012 Mutations of the EPHB6 receptor tyrosine kinase induce a pro-metastatic phenotype in non-small cell lung cancer. PloS one 24 23226491
2009 The kinase defective EPHB6 receptor tyrosine kinase activates MAP kinase signaling in lung adenocarcinoma. International journal of oncology 22 19513565
2019 EPHB6 mutation induces cell adhesion-mediated paclitaxel resistance via EPHA2 and CDH11 expression. Experimental & molecular medicine 21 31160603
2017 Reduced EphB6 protein in gastric carcinoma and associated lymph nodes suggests EphB6 as a gastric tumor and metastasis inhibitor. Cancer biomarkers : section A of Disease markers 18 28453458
2016 Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment. Oncotarget 18 27418135
2021 EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells. Cancers 17 33802447
2017 The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment. Scientific reports 16 29116180
2015 Expression of EphB6 in ovarian serous carcinoma is associated with grade, TNM stage and survival. Journal of clinical pathology 16 26468391
2016 EPHA7 and EPHA10 Physically Interact and Differentially Co-localize in Normal Breast and Breast Carcinoma Cell Lines, and the Co-localization Pattern Is Altered in EPHB6-expressing MDA-MB-231 Cells. Cancer genomics & proteomics 15 27566654
2014 Modulation of liver-intestine cadherin (Cadherin 17) expression, ERK phosphorylation and WNT signaling in EPHB6 receptor-expressing MDA-MB-231 cells. Cancer genomics & proteomics 15 25331796
2008 Identification of EphB6 variant-derived epitope peptides recognized by cytotoxic T-lymphocytes from HLA-A24+ malignant glioma patients. Oncology reports 15 18425388
2023 Integration of cancer-related genetic landscape of Eph receptors and ephrins with proteomics identifies a crosstalk between EPHB6 and EGFR. Cell reports 14 37392382
2017 iTRAQ-Based Proteomics Suggests Ephb6 as a Potential Regulator of the ERK Pathway in the Prefrontal Cortex of Chronic Social Defeat Stress Model Mice. Proteomics. Clinical applications 14 28967185
2016 The intrinsically kinase-inactive EPHB6 receptor predisposes cancer cells to DR5-induced apoptosis by promoting mitochondrial fragmentation. Oncotarget 14 27788485
2021 The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs. The Biochemical journal 13 34431498
2021 The EphB6 Receptor: Kinase-Dead but Very Much Alive. International journal of molecular sciences 11 34360976
2020 The PI3Kα inhibitor DFX24 suppresses tumor growth and metastasis in non-small cell lung cancer via ERK inhibition and EPHB6 reactivation. Pharmacological research 11 32814167
2021 Structure of the EphB6 receptor ectodomain. PloS one 10 33770085
2015 Clinical Significance of EphB4 and EphB6 Expression in Human Malignant and Benign Thyroid Lesions. Pathology oncology research : POR 10 26220827
2015 High expression of EphB6 protein in tongue squamous cell carcinoma is associated with a poor outcome. International journal of clinical and experimental pathology 10 26617870
2019 EPHB6 controls catecholamine biosynthesis by up-regulating tyrosine hydroxylase transcription in adrenal gland chromaffin cells. The Journal of biological chemistry 9 30824540
2018 EPHB6 and testosterone in concert regulate epinephrine release by adrenal gland chromaffin cells. Scientific reports 9 29339804
2023 Oat beta-glucan reduces colitis by promoting autophagy flux in intestinal epithelial cells via EPHB6-TFEB axis. Frontiers in pharmacology 8 37441529
2010 DNA-based assay for EPHB6 expression in breast carcinoma cells as a potential diagnostic test for detecting tumor cells in circulation. Cancer genomics & proteomics 8 20181626
2010 Tyrosine kinase-deficient EphB6 receptor-dependent alterations in proteomic profiles of invasive breast carcinoma cells as determined by difference gel electrophoresis. Cancer genomics & proteomics 8 20952760
2023 EphB6 deficiency in intestinal neurons promotes tumor growth in colorectal cancer by neurotransmitter GABA signaling. Carcinogenesis 7 37294054
2014 Ligand stimulation induces clathrin- and Rab5-dependent downregulation of the kinase-dead EphB6 receptor preceded by the disruption of EphB6-Hsp90 interaction. Cellular signalling 7 25152371
2023 Overexpression of EphB6 and EphrinB2 controls soma spacing of cortical neurons in a mutual inhibitory way. Cell death & disease 6 37149633
2016 NRAS and EPHB6 mutation rates differ in metastatic melanomas of patients in the North Island versus South Island of New Zealand. Oncotarget 6 27191502
2018 Analysis of the association of EPHB6, EFNB1 and EFNB3 variants with hypertension risks in males with hypogonadism. Scientific reports 4 30262919
2023 A functional role of Ephrin type-B receptor 6 (EPHB6) in T-cell acute lymphoblastic leukemia. Biomarker research 2 37858274
2020 The receptor tyrosine kinase EPHB6 regulates catecholamine exocytosis in adrenal gland chromaffin cells. The Journal of biological chemistry 2 32321761
2013 Acute DSS colitis alters EphB6 receptor expression in neurons of the spinal dorsal horn. Neuroscience letters 2 24309292
2024 Co-clustering of EphB6 and ephrinB1 in trans restrains cancer cell invasion. Communications biology 1 38627519
2026 SIAH2-EPHB6 axis enhances filopodia formation in hepatocellular carcinoma cells by regulating RHOF. Cell & bioscience 0 42036676
2024 Study on the Role of EPHB6 in Inhibiting the Malignant Progression of Cervical Cancer C33A Cells by Binding to CBX7. Cell biochemistry and biophysics 0 39322790

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