Affinage

EPHB4

Ephrin type-B receptor 4 · UniProt P54760

Length
987 aa
Mass
108.3 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EPHB4 is a transmembrane receptor tyrosine kinase of the EPH subfamily that autophosphorylates on tyrosine and is activated by its high-affinity ligand ephrinB2, with full receptor activation requiring membrane-bound or clustered ligand rather than monomeric soluble ligand (PMID:8188704, PMID:7534404, PMID:8761303). The selectivity of EPHB4 for ephrinB2 is structurally encoded by Leu-95 in its ligand-binding domain, where substitution to the arginine conserved in other Eph receptors alters ligand affinity (PMID:16867992). The central physiological role of EPHB4 is in vascular morphogenesis: it sorts venous from arterial endothelial cells and restricts inappropriate venous angiogenic growth (PMID:10603345, PMID:18952909), and its forward signaling suppresses RAS-MAPK and mTORC1 activity in endothelium through direct recruitment of RASA1 (p120 RasGAP), an interaction shown by RASA1-binding-deficient receptor mutants to be the functionally critical engagement for normal vessel development and collagen IV export from the endothelial ER (PMID:22555806, PMID:24837431, PMID:35015735). Loss of EPHB4 kinase function causes human vascular and lymphatic disease — capillary malformation–arteriovenous malformation type 2 (CM-AVM2) and lymphatic-related hydrops fetalis — with disease variants validated as kinase-dead and producing mTORC1/RAS-MAPK overactivation rescuable pharmacologically (PMID:28687708, PMID:27400125, PMID:29905864). EPHB4 kinase activity is likewise essential for lymphatic valve development and for collecting lymphatic vessel junction integrity via Rac1/Rho control of CLDN5 localization and contractility (PMID:25865237, PMID:32897857), and endothelial EphB4 maintains adult cardiac capillary integrity, caveolae function, and lipid transport (PMID:31782728). EPHB4 signals through multiple context-dependent effectors: tumor-suppressive Abl-Crk in breast cancer, pro-migratory RhoA, survival-promoting AKT, and STAT3 (PMID:16862147, PMID:16950769, PMID:16816380, PMID:26481148, PMID:36376513). In cancer it behaves as a context-dependent tumor suppressor in breast, intestinal, and head-and-neck tissue (PMID:16862147, PMID:19738063, PMID:35725568), while its extracellular domain can promote tumor angiogenesis independently of kinase activity (PMID:15067119). EPHB4 also coordinates bone homeostasis bidirectionally with ephrinB2 on osteoclast precursors (PMID:16890539) and regulates erythroid/megakaryocytic differentiation and HSPC mobilization through ephrinB2 on stroma and sinusoidal endothelium (PMID:11929761, PMID:27820703). Beyond ephrin ligands, EphB4 binds the insulin receptor directly via an AP2 motif to drive clathrin-mediated InsR degradation and modulate systemic insulin sensitivity (PMID:36131205).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1994 High

    Establishing that EPHB4 is an intrinsically active receptor tyrosine kinase defined its molecular class and the requirement for ligand or antibody engagement to drive phosphorylation.

    Evidence In vitro kinase assay with in vitro-translated protein plus agonist-antibody activation in transfected NIH3T3 cells

    PMID:8188704

    Open questions at the time
    • Physiological ligand not yet identified
    • Downstream effectors unknown
  2. 1996 High

    Identifying ephrinB2 as the high-affinity ligand and showing that only clustered/membrane-bound ligand activates the receptor established the cell-contact-dependent mode of EPHB4 signaling and its first functional output in hematopoietic progenitors.

    Evidence Receptor-Fc expression cloning, BIAcore affinity measurement, co-culture phosphorylation and progenitor proliferation assays

    PMID:7534404 PMID:8761303

    Open questions at the time
    • Downstream signaling cascade not defined
    • Whether forward vs reverse signaling drives each phenotype unresolved
  3. 2003 High

    Linking EPHB4 to erythroid/mesodermal differentiation and HoxA9-driven transcription defined developmental contexts and an upstream transcriptional regulator of the receptor.

    Evidence Sorted human progenitor co-cultures, EphB4-knockout ES cell differentiation, ChIP and reporter assays for HoxA9 promoter binding

    PMID:11929761 PMID:12051776 PMID:12958066 PMID:14764452 PMID:9108393

    Open questions at the time
    • Effector pathways linking EPHB4 activation to lineage commitment not mapped
    • Single-lab hematopoietic findings
  4. 2006 High

    Defining context-specific forward-signaling effectors — Abl-Crk tumor suppression, RhoA migration, AKT survival — and the structural basis of ligand selectivity reconciled EPHB4's divergent cellular outputs with a single receptor.

    Evidence Crystallography/ITC/mutagenesis of the EphB4–ephrinB2 interface; kinase-dead and dominant-negative epistasis; co-IP and knockdown across cancer cell systems

    PMID:16816380 PMID:16862147 PMID:16867992 PMID:16890539 PMID:16950769

    Open questions at the time
    • What dictates effector choice between tumor-suppressive and pro-tumorigenic outputs unresolved
    • AKT survival data medium confidence/single lab
  5. 2009 High

    Genetic and structure-function studies established EPHB4 as a tumor suppressor in vivo and revealed an ephrin-independent, kinase-dependent inhibition of integrin-mediated adhesion, expanding its mechanism beyond canonical ligand engagement.

    Evidence Apc(min)/EphB4+/- mouse tumor model and invasion assays; ephrin-binding-mutant and kinase-dead overexpression with integrin function assays

    PMID:19552627 PMID:19738063

    Open questions at the time
    • Mechanism of ephrin-independent kinase activation unknown
    • Substrates linking EPHB4 to integrin downregulation not identified
  6. 2014 High

    Identifying RASA1 as the direct EPHB4 effector that suppresses Ras/MAPK and mTORC1 in endothelium, validated by a RASA1-binding-deficient receptor that fails to rescue vascular defects, defined the core mechanism for normal angiogenesis.

    Evidence Engineered receptor rescue in zebrafish, mTORC1 pharmacological rescue, phospho-S6 in patient AVM tissue; PDGFRβ cross-activation co-IP in rhabdomyosarcoma

    PMID:22555806 PMID:24733895 PMID:24837431

    Open questions at the time
    • How EPHB4 toggles between RASA1 (ERK-suppressing) and PP2A/PDGFRβ (ERK-activating) couplings unresolved
  7. 2016 High

    Human genetics tied EPHB4 kinase loss-of-function to CM-AVM2 and lymphatic-related hydrops fetalis, and resolved that EPHB4 forward kinase signaling — not ephrinB2 reverse signaling — drives lymphatic valve development.

    Evidence Linkage/exome sequencing with in vitro kinase assays of disease variants; conditional Ephb4 lymphatic-endothelial knockout; EphB4-selective blocking antibody and chemical-genetic kinase-dead approach

    PMID:25865237 PMID:26481148 PMID:27400125 PMID:27820703 PMID:28687708

    Open questions at the time
    • How identical kinase loss produces distinct CM-AVM2 vs LRHF phenotypes unresolved
    • Epo/STAT3 receptor role medium confidence/single lab
  8. 2019 High

    Tissue-specific conditional knockouts revealed organ-restricted endothelial requirements — cardiac capillary integrity, caveolae, and lipid transport — distinguishing EPHB4 functions across vascular beds.

    Evidence Inducible endothelial-specific Ephb4 knockout with echocardiography, caveolae EM, junction and lipid transport assays; metabolic/ER-stress assays in prostate cancer

    PMID:28371279 PMID:29643120 PMID:31641103 PMID:31782728

    Open questions at the time
    • Molecular basis of cardiac- vs skeletal-muscle capillary selectivity unknown
    • Link between EPHB4 and caveolae/lipid machinery not defined at the effector level
  9. 2022 High

    Mechanistic dissection established RASA1 engagement as the key interaction enabling collagen IV ER export in angiogenesis and uncovered a non-ephrin role for EPHB4 in promoting insulin receptor degradation via an AP2 motif.

    Evidence EC-specific knockout with RASA1-binding-mutant knock-in and collagen IV ER-export rescue; EphB4–InsR co-IP, AP2 motif mapping, clathrin endocytosis/degradation assays and hepatic in vivo manipulation; lymphatic junction and HNSCC/CRC tumor models

    PMID:32897857 PMID:35015735 PMID:35725568 PMID:36131205 PMID:36376513

    Open questions at the time
    • How kinase activity, RASA1 binding, and AP2-mediated trafficking are coordinated in a single receptor unresolved
    • Generality of InsR degradation role beyond liver not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular switch determines whether EPHB4 acts as a tumor suppressor (Abl-Crk, RASA1) or tumor promoter (AKT, STAT3, extracellular-domain angiogenesis) in a given cellular context.
  • No unifying model linking effector selection to cell state
  • Determinants of ephrin-dependent vs ephrin-independent signaling not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 2 GO:0001618 virus receptor activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-5653656 Vesicle-mediated transport 1
Partners
ABL1AP2CRKEFNB2INSRPDGFRBRASA1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 EPHB4 (HTK) is a transmembrane receptor tyrosine kinase of the EPH subfamily that autophosphorylates on tyrosine in in vitro kinase assays; agonistic antibodies against its extracellular domain induce tyrosine phosphorylation in transfected NIH3T3 cells, establishing its intrinsic kinase activity. In vitro kinase assay with purified in vitro-translated protein; antibody-mediated receptor activation in transfected cells; subcellular fractionation showing membrane localization The Journal of biological chemistry High 8188704
1995 A transmembrane protein ligand (HTKL/ephrinB2) binds EPHB4 (Htk) with high affinity (Kd ~535 pM) and induces tyrosine phosphorylation of EPHB4; membrane-bound or clustered soluble ligand is required for receptor activation, whereas unclustered soluble ligand is insufficient. Receptor-Fc fusion protein expression cloning; binding competition assay; co-culture tyrosine phosphorylation assay Proceedings of the National Academy of Sciences of the United States of America High 7534404
1996 Membrane-bound or clustered HTKL (ephrinB2) induces HTK (EPHB4) receptor tyrosine phosphorylation and stimulates proliferation of HTK+ hematopoietic progenitor cells; high-affinity binding (Kd ~1.23 nM) established by BIAcore; unclustered soluble ligand does not activate the receptor. BIAcore affinity measurement; receptor phosphorylation assay; proliferation assay of sorted HTK+ cord blood cells Oncogene High 8761303
1997 EPHB4 (HTK) is selectively expressed on human erythroid progenitor cells (predominantly BFU-E stage) in bone marrow, while its ligand ephrinB2 is expressed on bone marrow stromal cells, establishing a stromal–progenitor signaling axis for erythropoiesis. Monoclonal antibody generation; flow cytometry of bone marrow fractions; progenitor colony assays; co-culture with stromal cells Blood Medium 9108393
2000 EphB4 restricts angiogenic growth of embryonic veins in Xenopus laevis; dominant-negative EphB4 or misexpression of ephrin-B ligands causes intersomitic veins to grow abnormally into adjacent somitic tissue, indicating EphB4 mediates repulsive guidance cues to migrating endothelial cells. RNA injection of dominant-negative EphB4 into Xenopus embryos; ephrin-B misexpression; in situ hybridization for expression patterns Development (Cambridge, England) High 10603345
2002 EphB4 signaling promotes erythroid differentiation; co-culture of EphB4+ hematopoietic progenitors with ephrin-B2-expressing stromal cells causes rapid detachment from stroma and differentiation to mature erythroid cells with concurrent EphB4 downregulation; ephrin-B2 expression on endothelial cells is upregulated under hypoxia. Co-culture assay of sorted CD34+/c-Kit+ cord blood cells on stromal cell lines ± ephrin-B2; flow cytometry for differentiation markers Biochemical and biophysical research communications Medium 12051776
2002 Ectopic EphB4 expression in hematopoietic cell lines promotes megakaryocytic differentiation but not granulocytic or monocytic differentiation; EphB4 depletes primitive progenitors and increases committed progenitors; these effects require intact tyrosine kinase activity since mutation of select tyrosine residues or treatment with genistein abrogates them. Retroviral transduction of EphB4 into cell lines and primary CD34+ cord blood cells; flow cytometry for lineage markers; LTC-IC assay; tyrosine-site mutagenesis; kinase inhibitor treatment Blood High 11929761
2003 EphB4 regulates ES cell differentiation into mesodermal lineages including hemangioblasts, blood cells, cardiomyocytes, and vascular cells; EphB4−/− ES cells show impaired acquisition of mesoderm-associated gene expression and phenotypes but not neuroectoderm-associated features. EphB4 knockout ES cell differentiation assay; gene expression profiling; phenotypic characterization of mesodermal vs. neuroectodermal markers Blood High 12958066
2004 HoxA9 transcription factor directly binds the EPHB4 promoter (confirmed by ChIP) and activates EPHB4 transcription; downregulation of HoxA9 reduces EphB4 expression and impairs endothelial cell tube formation and migration. Chromatin immunoprecipitation (ChIP); reporter gene assay; HoxA9 siRNA knockdown; endothelial tube formation and migration assays Circulation research High 14764452
2004 EphB4 promotes tumor angiogenesis through its extracellular domain interacting with ephrin-B2 on vascular endothelium; kinase-domain-deleted EphB4 on breast cancer cells still increases tumor growth by stimulating endothelial cell invasion, survival, and proliferation in vitro, indicating the extracellular domain is sufficient for pro-angiogenic effects. Kinase-domain-deleted EphB4-EGFP expression in xenograft model; endothelial chemotaxis and invasion assays; blood vessel morphometry in tumors Proceedings of the National Academy of Sciences of the United States of America Medium 15067119
2006 Crystal structure of the EphB4 ligand-binding domain in complex with the ephrinB2 extracellular domain reveals that Leu-95 in EphB4 (vs. conserved Arg in other Eph receptors) is the key determinant of EphB4's high selectivity for ephrinB2; L95R mutation alters binding affinity for ephrinB2 and an antagonistic peptide. Isothermal titration calorimetry shows ephrinB2 binding is entropy-driven whereas peptide binding is enthalpy-driven. X-ray crystallography; site-directed mutagenesis (L95R and other variants); isothermal titration calorimetry (ITC) The Journal of biological chemistry High 16867992
2006 EphB4 acts as a tumor suppressor in breast cancer by activating an Abl-Crk signaling pathway upon ephrin-B2 stimulation; this pathway inhibits breast cancer cell viability, proliferation, motility, invasion, and downregulates MMP-2; the Abl-Crk pathway is constitutively active in non-transformed mammary epithelial cells. Xenograft tumor model; siRNA knockdown; Abl kinase activity assays; Crk co-immunoprecipitation; MMP-2 zymography; cell viability and invasion assays Nature cell biology High 16862147
2006 EphB4 forward signaling through ephrinB2 stimulation promotes melanoma cell migration by activating RhoA, which reorganizes the actin cytoskeleton; kinase-dead EphB4 inhibits migration and disrupts actin organization; dominant-negative RhoA blocks EphB4-mediated migration enhancement. EphB4 overexpression, kinase-dead mutant, and dominant-negative RhoA in melanoma cells; Boyden chamber migration assay; RhoA activity (pull-down) assay; actin staining The Journal of biological chemistry High 16950769
2006 EphB4 provides a survival signal to breast cancer cells through phosphorylation via ephrinB2 and activation of the AKT (protein kinase B) pathway; EphB4 knockdown by siRNA or antisense ODN induces apoptosis, reduces AKT phosphorylation, and sensitizes cells to TRAIL-mediated death. siRNA and antisense ODN knockdown; Western blot for phospho-AKT; apoptosis and viability assays; xenograft tumor model The American journal of pathology Medium 16816380
2006 Bidirectional ephrinB2-EphB4 signaling coordinates bone homeostasis: reverse signaling through ephrinB2 (expressed on osteoclast precursors) suppresses osteoclast differentiation by inhibiting the c-Fos-NFATc1 cascade; forward signaling through EphB4 (expressed on osteoblasts) enhances osteogenic differentiation; EphB4 overexpression in osteoblasts increases bone mass in transgenic mice. Gain- and loss-of-function in vitro differentiation assays; transgenic EphB4 overexpression in osteoblasts; bone histomorphometry; gene expression analysis of NFATc1 and c-Fos Cell metabolism High 16890539
2008 Loss of ephrinB2 or EphB4 in mice causes enlarged aortae and underdeveloped cardinal veins with venous-identity endothelial cells mislocalized into the aorta, demonstrating that ephrinB2/EphB4 signaling functions by sorting arterial and venous endothelial cells into their respective vessels (distinct from the Notch pathway which controls the proportion of arterial vs. venous cells). Genetic loss-of-function mouse embryo analysis; endothelial cell identity marker staining; comparison with Notch gain/loss-of-function Development (Cambridge, England) High 18952909
2009 EphB4 inhibits integrin-mediated cell-substrate adhesion, spreading, and migration in an ephrin-independent, kinase-activity-dependent manner in cancer cells; EphB4 reduces β1-integrin protein levels; mutations abolishing ephrin binding do not affect adhesion inhibition, but kinase activity is required. siRNA knockdown of EphB4 in MCF7 and MDA-MB-435 cells; transient overexpression with ephrin-binding mutants; integrin function assays (adhesion, spreading, migration); β1-integrin protein measurement The Biochemical journal High 19552627
2009 EphB4 has tumor suppressor activity in intestinal tumorigenesis; hemizygous inactivation of EphB4 in Apc(min) mice results in higher proliferation, larger tumors in the small intestine, 10-fold more tumors in the large intestine, and 25% shorter lifespan; loss of EphB4 in colon cancer cells increases invasive potential through extracellular matrix. Apc(min)/EphB4+/− genetic mouse model; xenograft model with EphB4 modulation; invasion assay through complex extracellular matrix; gene expression profiling Cancer research High 19738063
2012 EphB4 activation has context-dependent effects on the Ras/MEK/ERK pathway: it inhibits ERK in endothelial cells (HUVECs) via functional coupling to p120 RasGAP, but activates ERK in MCF-7 breast cancer cells via functional coupling to PP2A; knockdown of p120 RasGAP attenuates ERK inhibition in HUVECs, while PP2A knockdown attenuates ERK activation in MCF-7 cells. EphrinB2 stimulation and agonist antibody treatment; ERK phosphorylation Western blots; siRNA knockdown of p120 RasGAP and PP2A; cell proliferation assays Cancer biology & therapy Medium 22555806
2014 RASA1 (p120 RasGAP) functions as a direct downstream effector of EPHB4 in endothelial cells to suppress mTORC1 activity; engineered EPHB4 receptors unable to recruit RASA1 cannot rescue vascular defects in EPHB4-deficient zebrafish; EPHB4 or RASA1 deficiency causes mTORC1 overactivation, and mTORC1 inhibition rescues vessel structure and function. EPHB4 engineered receptor rescue experiments in zebrafish; pharmacological mTORC1 inhibition; phospho-S6 staining in patient AVM tissue; zebrafish EPHB4/RASA1 knockdown models The Journal of clinical investigation High 24837431
2014 PDGFRβ cross-activates EphB4 in a PDGF ligand-dependent, ephrin ligand-independent manner in alveolar rhabdomyosarcoma cells, converging on Akt and Erk1/2 pathways to promote survival; conversely, ephrinB2-mediated EphB4 activation paradoxically induces apoptosis in these cells. RNAi kinome screen in primary aRMS cultures; co-immunoprecipitation of PDGFRβ-EphB4; phosphorylation assays; apoptosis assays; dasatinib treatment in vitro and in vivo xenograft Proceedings of the National Academy of Sciences of the United States of America Medium 24733895
2015 EphB4 forward signaling is required for lymphatic valve development; selective pharmacological inhibition of EphB4 using a function-blocking antibody causes defective lymphatic valve development; chemical genetic experiments confirm that EphB4 kinase activity is essential for this process; prior assignment of this role to ephrinB2 reverse signaling was due to altered EphB4 forward signaling in ephrinB2 cytoplasmic-mutant mice. EphB4-selective blocking antibody; ephrinB2-selective blocking antibody; chemical genetic kinase-dead knockin approach; lymphatic valve morphology analysis Nature communications High 25865237
2015 EphB4 functions as an alternative erythropoietin (Epo) receptor on tumor cells, triggering STAT3 signaling downstream and promoting rhEpo-induced tumor growth and progression; this is distinct from the canonical EpoR. EphB4 identification as Epo-binding receptor; STAT3 phosphorylation assays upon Epo stimulation; EphB4 knockdown/overexpression in tumor cell lines; xenograft models Cancer cell Medium 26481148
2016 EPHB4 loss-of-function mutations cause capillary malformation-arteriovenous malformation type 2 (CM-AVM2) by deregulating RAS-MAPK signaling; in vitro expression of missense variants confirmed loss of kinase function; RASA1 (p120 RasGAP), a direct effector of EPHB4, links EPHB4 to RAS-ERK pathway control in endothelium. Genome-wide linkage study; whole-exome sequencing; in vitro expression and phosphorylation assays for missense variants; family segregation analysis Circulation High 28687708
2016 EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis (LRHF); mutant EPHB4 proteins are devoid of tyrosine kinase activity; inactivation of Ephb4 in mouse lymphatic endothelial cells causes defective lymphovenous valve formation and subcutaneous edema. Exome sequencing; in vitro biochemical kinase activity assays of mutant proteins; conditional Ephb4 knockout in mouse lymphatic endothelial cells; lymphatic valve morphology assessment The Journal of clinical investigation High 27400125
2016 EPHB4 on bone marrow sinusoidal endothelium interacts with ephrinB2 on hematopoietic cells to control HSPC mobilization from bone marrow; blockade of the EPHB4/ephrinB2 signaling pathway reduces HSPC and myeloid cell mobilization to circulation and reduces HSPC infiltration into tumors. EPHB4 and ephrinB2 expression mapping in bone marrow by immunostaining; pharmacological blockade of EPHB4/ephrinB2 interaction; HSPC mobilization assays; tumor progression models in mice The Journal of clinical investigation Medium 27820703
2017 EphB4 forward signaling mediates angiogenesis caused by CCM3/PDCD10 ablation; CCM3 silencing upregulates EphB4 expression and kinase activity with concurrent Erk1/2 activation; EphB4 kinase inhibition rescues the hyper-angiogenic phenotype; DLL4/Notch signaling acts upstream of EphB4 in this pathway: CCM3-DLL4/Notch-EphB4-Erk1/2. CCM3 siRNA knockdown; EphB4 kinase inhibitor (NVP-BHG712); in vitro tube formation and in vivo angiogenesis assays; Western blot for EphB4 and p-Erk1/2 Journal of cellular and molecular medicine Medium 28371279
2018 EphB4 pathogenic variant (splice-site mutation causing intron retention) results in reduced tyrosine phosphorylation (loss-of-function); reduced EPHB4 signaling leads to mTORC1 over-activation in zebrafish and HEK293T knock-in cells; mTOR or RAS-MAPK inhibitors rescue the vascular misbranching phenotype in zebrafish. Whole exome sequencing; RNA-Seq splice analysis; co-expression of WT and mutant EPHB4 with phosphorylation assay; zebrafish morpholino knockdown; mTORC1 pathway Western blots; pharmacological rescue Human molecular genetics High 29905864
2018 EphB4 modulates VEGF-R2 downstream ERK1/2 signaling (but not VEGF-R2 activation or internalization per se) to regulate the degree of endothelial proliferation during intussusceptive (non-sprouting) angiogenesis; in vivo ERK1/2 inhibition abolishes EphB4 regulation of VEGF-induced intussusception. In vivo adenoviral VEGF delivery; EphB4 pharmacological stimulation; VEGF-R2 activation and internalization assays; phospho-ERK1/2 measurements; ERK1/2 inhibitor experiments in vivo EMBO reports Medium 29643120
2019 EPHB4 inhibition reduces GLUT3 expression, impairs glucose uptake, decreases ATP levels, and activates endoplasmic reticulum stress with features of immunogenic cell death (eIF2α phosphorylation, calreticulin surface exposure, HMGB1 and ATP release) in prostate cancer cells; metabolic changes are associated with MYC downregulation via SRC/p38 MAPK/4EBP1 signaling. EPHB4 pharmacological inhibition and siRNA; glucose uptake assays; ATP measurement; Western blots for ER stress markers; calreticulin surface staining; HMGB1/ATP release assays Cell death & disease Medium 31641103
2019 Endothelial EphB4 is required for cardiac capillary integrity, caveolae function, cell-cell adhesion under mechanical stress, and lipid transport in the adult heart; inducible endothelial-specific Ephb4 inactivation causes cardiac capillary rupture, cardiomyocyte hypertrophy, and dilated cardiomyopathy-like pathological remodeling, but EphB4 is dispensable for integrity of skeletal muscle capillaries. Inducible endothelial cell-specific Ephb4 conditional knockout; cardiac imaging (echocardiography); electron microscopy of caveolae; endothelial junction analysis; lipid transport assay eLife High 31782728
2020 EphrinB2/EphB4 signaling maintains collecting lymphatic vessel junction integrity through Rac1/Rho-mediated regulation of cytoskeletal contractility and junctional localization of the tight junction protein CLDN5; EphrinB2/EphB4 is dispensable for blood endothelial barrier function but required for lymphatic endothelial cell junction stability. Conditional gene deletion in mice; primary human LEC culture; CLDN5 localization by immunofluorescence; Rac1/Rho activity assays; cytoskeletal inhibitor treatments eLife High 32897857
2022 EphB4 promotes normal angiogenesis by enabling collagen IV export from the endothelial cell ER; EC-specific Ephb4 disruption causes collagen IV accumulation in the ER, EC apoptosis, and defective angiogenesis; drugs promoting collagen IV ER export rescue this phenotype; an EPHB4 mutant unable to physically engage RASA1 but retaining kinase activity shows normal angiogenesis, indicating RASA1 engagement is the key functional interaction. Inducible EC-specific Ephb4 conditional knockout; drugs inhibiting Ras pathway signaling or promoting collagen IV ER export as rescue experiments; RASA1-binding mutant EPHB4 knock-in; collagen IV localization in ER by immunofluorescence JCI insight High 35015735
2022 EphB4 binds directly to the insulin receptor (InsR), and this interaction is markedly enhanced by insulin; EphB4 contains an AP2 complex-binding motif that facilitates clathrin-mediated InsR endocytosis and lysosomal degradation; hepatic EphB4 overexpression decreases InsR levels and increases insulin resistance, while EphB4 inhibition improves insulin resistance in obese mice. Co-immunoprecipitation of EphB4 and InsR; AP2 binding motif identification; clathrin-mediated endocytosis assay; lysosomal degradation assay; hepatic overexpression and genetic/pharmacological inhibition in mice; insulin tolerance and glucose tolerance tests Nature metabolism High 36131205
2022 EphrinB2 on cancer cells and vasculature acts as a tumor promoter in HNSCC while EphB4 acts as a tumor suppressor; EphB4 knockdown on cancer cells accelerates tumor growth and angiogenesis and triggers compensatory EphA4 upregulation and regulatory T cell influx; ephrinB2 knockout reduces tumor growth and promotes vascular normalization; EphB4 agonism provides no anti-tumoral benefit without ephrinB2. Genetically engineered mouse models; EphB4/ephrinB2 agonist and antagonist pharmacological treatment; EphA4 expression analysis; Treg flow cytometry; tumor volume measurement; vascular normalization histology Nature communications High 35725568
2022 The EFNB2/EPHB4 axis in colorectal cancer liver metastases promotes LDLR-mediated cholesterol uptake by regulating STAT3 phosphorylation, which drives LDLR transcription; blocking LDLR reverses the tumor-promoting effects of EFNB2/EPHB4. EFNB2/EPHB4 knockdown and overexpression in CRC cell lines; STAT3 phosphorylation Western blot; LDLR promoter activity assay; cholesterol uptake assay; in vivo liver metastasis models Oncogene Medium 36376513

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell metabolism 598 16890539
2006 The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nature cell biology 250 16862147
2004 Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth. Proceedings of the National Academy of Sciences of the United States of America 212 15067119
2017 Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling. Circulation 211 28687708
2006 Receptor tyrosine kinase EphB4 is a survival factor in breast cancer. The American journal of pathology 167 16816380
2005 EphB4 expression and biological significance in prostate cancer. Cancer research 132 15930280
2009 Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression. Cancer research 120 19366806
2007 Paradoxes of the EphB4 receptor in cancer. Cancer research 115 17483308
2004 Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation. Circulation research 111 14764452
2000 The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis. Development (Cambridge, England) 110 10603345
2004 Inhibition of tumor growth and angiogenesis by soluble EphB4. Neoplasia (New York, N.Y.) 108 15153337
2004 Expression of Ephb2 and Ephb4 in breast carcinoma. Pathology oncology research : POR 104 15029258
1995 Molecular cloning of a ligand for the EPH-related receptor protein-tyrosine kinase Htk. Proceedings of the National Academy of Sciences of the United States of America 103 7534404
2008 Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis. Development (Cambridge, England) 98 18952909
2015 Erythropoietin Stimulates Tumor Growth via EphB4. Cancer cell 86 26481148
2001 Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer. BMC molecular biology 86 11801186
2006 EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival. Oncogene 85 16205642
1996 Characterization of a ligand for receptor protein-tyrosine kinase HTK expressed in immature hematopoietic cells. Oncogene 85 8761303
2006 Structural and biophysical characterization of the EphB4*ephrinB2 protein-protein interaction and receptor specificity. The Journal of biological chemistry 84 16867992
2006 The EphB4 receptor-tyrosine kinase promotes the migration of melanoma cells through Rho-mediated actin cytoskeleton reorganization. The Journal of biological chemistry 84 16950769
2016 EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis. The Journal of clinical investigation 81 27400125
2015 Erythropoietin promotes bone formation through EphrinB2/EphB4 signaling. Journal of dental research 79 25586589
2006 EphB2 and EphB4 receptors forward signaling promotes SDF-1-induced endothelial cell chemotaxis and branching remodeling. Blood 78 16840724
2015 EphB4 forward signalling regulates lymphatic valve development. Nature communications 77 25865237
2018 Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly. Human molecular genetics 74 29905864
1994 Cloning and characterization of HTK, a novel transmembrane tyrosine kinase of the EPH subfamily. The Journal of biological chemistry 74 8188704
2010 Novel EphB4 monoclonal antibodies modulate angiogenesis and inhibit tumor growth. The American journal of pathology 72 20133814
2018 EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF. EMBO reports 70 29643120
2006 EPHB4 and survival of colorectal cancer patients. Cancer research 70 16982731
2014 RASA1 functions in EPHB4 signaling pathway to suppress endothelial mTORC1 activity. The Journal of clinical investigation 68 24837431
2006 EphB4 provides survival advantage to squamous cell carcinoma of the head and neck. International journal of cancer 68 16615113
2013 The EphB4 receptor tyrosine kinase promotes lung cancer growth: a potential novel therapeutic target. PloS one 63 23844053
2002 A role of EphB4 receptor and its ligand, ephrin-B2, in erythropoiesis. Biochemical and biophysical research communications 60 12051776
2012 EphB4 promotes or suppresses Ras/MEK/ERK pathway in a context-dependent manner: Implications for EphB4 as a cancer target. Cancer biology & therapy 58 22555806
2010 Communication between ephrinB2 and EphB4 within the osteoblast lineage. Advances in experimental medicine and biology 58 19950015
2008 Coexpression of EphB4 and ephrinB2 in tumour advancement of ovarian cancers. British journal of cancer 57 18231102
2017 Targeting receptor tyrosine kinase EphB4 in cancer therapy. Seminars in cancer biology 56 28993206
2009 The receptor tyrosine kinase EPHB4 has tumor suppressor activities in intestinal tumorigenesis. Cancer research 56 19738063
2009 Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor. The Biochemical journal 52 19552627
2002 Evaluation of rat liver apoptotic and necrotic cell death after cold storage using UW, HTK, and Celsior. Transplantation 51 12352902
2016 EphrinB2/EphB4 pathway in postnatal angiogenesis: a potential therapeutic target for ischemic cardiovascular disease. Angiogenesis 49 27216867
2020 EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity. eLife 48 32897857
2003 Activation of the receptor protein tyrosine kinase EphB4 in endometrial hyperplasia and endometrial carcinoma. Annals of oncology : official journal of the European Society for Medical Oncology 48 12562648
2019 Endothelial EphB4 maintains vascular integrity and transport function in adult heart. eLife 47 31782728
2019 EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells. Cell death & disease 46 31641103
2003 Ephrin receptor, EphB4, regulates ES cell differentiation of primitive mammalian hemangioblasts, blood, cardiomyocytes, and blood vessels. Blood 45 12958066
2012 Critical role for the receptor tyrosine kinase EPHB4 in esophageal cancers. Cancer research 44 23100466
2015 The tumour-promoting receptor tyrosine kinase, EphB4, regulates expression of integrin-β8 in prostate cancer cells. BMC cancer 43 25886373
2014 Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation. The Journal of international medical research 42 24517927
2020 The critical role of the interplays of EphrinB2/EphB4 and VEGF in the induction of angiogenesis. Molecular biology reports 41 32488576
2010 EphB4 promotes site-specific metastatic tumor cell dissemination by interacting with endothelial cell-expressed ephrinB2. Molecular cancer research : MCR 41 21047731
2006 Overexpression of ephrinB2 and EphB4 in tumor advancement of uterine endometrial cancers. Annals of oncology : official journal of the European Society for Medical Oncology 41 17108150
2005 Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma. BMC cancer 41 16171530
2005 Up-regulation of EphB4 in mesothelioma and its biological significance. Clinical cancer research : an official journal of the American Association for Cancer Research 40 15958611
2021 Sanguinarine combats hypoxia-induced activation of EphB4 and HIF-1α pathways in breast cancer. Phytomedicine : international journal of phytotherapy and phytopharmacology 39 33636580
2002 Receptor tyrosine kinase, EphB4 (HTK), accelerates differentiation of select human hematopoietic cells. Blood 39 11929761
1997 Selective expression of the receptor tyrosine kinase, HTK, on human erythroid progenitor cells. Blood 39 9108393
2016 EphB4 promotes the proliferation, invasion, and angiogenesis of human colorectal cancer. Experimental and molecular pathology 38 27072105
2020 CircRNA EPHB4 modulates stem properties and proliferation of gliomas via sponging miR-637 and up-regulating SOX10. Molecular oncology 37 33085838
2017 EphB4 forward signalling mediates angiogenesis caused by CCM3/PDCD10-ablation. Journal of cellular and molecular medicine 35 28371279
2016 Sinusoidal ephrin receptor EPHB4 controls hematopoietic progenitor cell mobilization from bone marrow. The Journal of clinical investigation 35 27820703
2009 Soluble EphB4 inhibition of PDGF-induced RPE migration in vitro. Investigative ophthalmology & visual science 35 19696168
2005 Soluble EphB4 regulates choroidal endothelial cell function and inhibits laser-induced choroidal neovascularization. Investigative ophthalmology & visual science 35 16303978
2019 Antitumor effects of circ-EPHB4 in hepatocellular carcinoma via inhibition of HIF-1α. Molecular carcinogenesis 34 30644610
2014 PDGFRβ reverses EphB4 signaling in alveolar rhabdomyosarcoma. Proceedings of the National Academy of Sciences of the United States of America 33 24733895
2018 Long noncoding RNA BC005927 upregulates EPHB4 and promotes gastric cancer metastasis under hypoxia. Cancer science 32 29383777
2013 EphB4 as a therapeutic target in mesothelioma. BMC cancer 32 23721559
2019 Homoharringtonine suppresses LoVo cell growth by inhibiting EphB4 and the PI3K/AKT and MAPK/EKR1/2 signaling pathways. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 31 31726078
2015 EphB4 Expressing Stromal Cells Exhibit an Enhanced Capacity for Hematopoietic Stem Cell Maintenance. Stem cells (Dayton, Ohio) 31 26033476
2020 Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated β-catenin loss in hepatocellular carcinoma. Cell death & disease 30 32801343
2022 Angiogenesis depends upon EPHB4-mediated export of collagen IV from vascular endothelial cells. JCI insight 29 35015735
2019 EphrinB2/EphB4 Signaling Regulates DPSCs to Induce Sprouting Angiogenesis of Endothelial Cells. Journal of dental research 29 31017515
2018 Claudin 11 regulates bone homeostasis via bidirectional EphB4-EphrinB2 signaling. Experimental & molecular medicine 29 29700355
2022 Insulin induces insulin receptor degradation in the liver through EphB4. Nature metabolism 28 36131205
2016 KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors. Molecular and cellular biology 28 27273865
2013 PET imaging of colorectal and breast cancer by targeting EphB4 receptor with 64Cu-labeled hAb47 and hAb131 antibodies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 27 23667241
2007 EphB4 expression along adult rat microvascular networks: EphB4 is more than a venous specific marker. Microcirculation (New York, N.Y. : 1994) 25 17454677
2009 Imidazo[1,2-a]pyrazine diaryl ureas: inhibitors of the receptor tyrosine kinase EphB4. Bioorganic & medicinal chemistry letters 24 19879134
2014 Arterial shear stress reduces eph-b4 expression in adult human veins. The Yale journal of biology and medicine 23 25191151
2012 Fluorine-18 radiolabeling and radiopharmacological characterization of a benzodioxolylpyrimidine-based radiotracer targeting the receptor tyrosine kinase EphB4. ChemMedChem 23 23042640
2022 Adaptive activation of EFNB2/EPHB4 axis promotes post-metastatic growth of colorectal cancer liver metastases by LDLR-mediated cholesterol uptake. Oncogene 22 36376513
2016 Enhancing radiosensitization in EphB4 receptor-expressing Head and Neck Squamous Cell Carcinomas. Scientific reports 22 27941840
2015 Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer. Scientific reports 22 26073592
2015 Specific photothermal therapy to the tumors with high EphB4 receptor expression. Biomaterials 22 26264644
2010 Over-expression of Ephb4 is associated with carcinogenesis of gastric cancer. Digestive diseases and sciences 22 20686847
2005 Differential expression of the receptor tyrosine kinase EphB4 and its ligand Ephrin-B2 during human placental development. Placenta 22 16343615
2003 Expression of EphB4 in head and neck squamous cell carcinoma. Ear, nose, & throat journal 22 14661437
1999 Expression of receptor tyrosine kinase HTK (hepatoma transmembrane kinase) and HTK ligand by human leukemia-lymphoma cell lines. Leukemia & lymphoma 22 10221518
2022 EphrinB2-EphB4 Signaling in Neurooncological Disease. International journal of molecular sciences 21 35163601
2022 EphB4 and ephrinB2 act in opposition in the head and neck tumor microenvironment. Nature communications 21 35725568
2018 EphB4: A promising target for upper aerodigestive malignancies. Biochimica et biophysica acta. Reviews on cancer 20 29369779
2012 Targeting the EphB4 receptor for cancer diagnosis and therapy monitoring. Molecular pharmaceutics 20 23211050
2012 Reduced adult endothelial cell EphB4 function promotes venous remodeling. American journal of physiology. Cell physiology 20 23269240
2023 M6PR- and EphB4-Rich Exosomes Secreted by Serglycin-Overexpressing Esophageal Cancer Cells Promote Cancer Progression. International journal of biological sciences 19 36632458
2022 ED-71 inhibited osteoclastogenesis by enhancing EphrinB2-EphB4 signaling between osteoclasts and osteoblasts in osteoporosis. Cellular signalling 19 35690294
2017 EPHB4 is a therapeutic target in AML and promotes leukemia cell survival via AKT. Blood advances 19 29296810
2014 EPHB4 tyrosine-kinase receptor expression and biological significance in soft tissue sarcoma. International journal of cancer 19 25274141
2019 Pancreatic Tumor Microenvironment Modulation by EphB4-ephrinB2 Inhibition and Radiation Combination. Clinical cancer research : an official journal of the American Association for Cancer Research 18 30944125
2014 Overexpression of EphB4, EphrinB2, and epidermal growth factor receptor in papillary thyroid carcinoma: A pilot study. Head & neck 18 24634162
2012 EphB4 is overexpressed in gliomas and promotes the growth of glioma cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 18 23138393

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