Affinage

EPHB2

Ephrin type-B receptor 2 · UniProt P29323

Length
1055 aa
Mass
117.5 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EphB2 is a receptor tyrosine kinase that transduces bidirectional signals upon binding ephrin-B and ephrin-A5 ligands, governing cell positioning, proliferation, invasion, synaptic plasticity, and tissue fibrosis through separable kinase-dependent and kinase-independent pathways. Its kinase activity drives proliferation via Abl–cyclin D1, invasion via FAK and MMP induction, and memory consolidation via CREB phosphorylation, whereas kinase-independent signaling through PI3K controls cell migration and NMDA receptor-dependent synaptic function by regulating surface NR1/NR2B subunit levels (PMID:19914164, PMID:11754836, PMID:11754835, PMID:29768201). EphB2 is post-translationally regulated by Src binding at phospho-Y611, RNF186-mediated ubiquitination at K892 triggering LC3-dependent autophagy, and context-dependent proteolytic processing by ADAM10 and γ-secretase (PMID:9632142, PMID:33280498, PMID:17428795). Beyond the nervous system, EphB2 promotes hepatic stellate cell activation and fibrosis, drives cancer stemness through a SRC/AKT/β-catenin feedback loop, and mediates Notch-dependent hepatocyte inflammation in NASH (PMID:25784101, PMID:33903122, PMID:36753562).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1998 High

    Identifying how EphB2 kinase activity is regulated: autophosphorylation at Y611 creates a docking site for Src-SH2, establishing Src as a proximal downstream effector and defining the juxtamembrane region as a regulatory hub.

    Evidence Yeast two-hybrid, site-directed mutagenesis, co-IP from transfected COS cells, phosphopeptide mapping

    PMID:9632142

    Open questions at the time
    • Whether Src is required for all EphB2 downstream outputs was not tested
    • Other SH2-domain effectors recruited to the juxtamembrane region remain uncharacterized
  2. 2001 High

    Resolving whether EphB2 kinase activity is required for synaptic function: full-receptor knockout but not kinase-domain deletion impaired NMDA currents and LTP, establishing that EphB2 regulates synaptic plasticity and NMDA receptor localization through a kinase-independent mechanism.

    Evidence EphB2 knockout vs. kinase-domain truncation knock-in mice, electrophysiology, immunogold NR1 localization

    PMID:11754835 PMID:11754836

    Open questions at the time
    • The extracellular/juxtamembrane domain partners mediating kinase-independent synaptic effects were not identified
    • Whether the kinase-independent pathway operates through PI3K at the synapse was unknown
  3. 2004 High

    Demonstrating cross-class ligand recognition: EphB2 binds ephrin-A5 as a heterodimer (not tetramer), inducing autophosphorylation and growth cone collapse, expanding the repertoire of activating ligands beyond ephrin-B family members.

    Evidence X-ray crystallography of ephrin-A5–EphB2 complex, cell-based autophosphorylation and neurite retraction assays

    PMID:15107857

    Open questions at the time
    • Physiological contexts where cross-class signaling predominates over canonical ephrin-B signaling are undefined
    • Downstream pathway divergence between ephrin-A5 and ephrin-B2 stimulation was not assessed
  4. 2004 High

    Linking EphB2 to cancer cell invasion: activated EphB2 localizes to lamellipodia and promotes glioma migration and invasion, establishing a pro-invasive role for EphB2 kinase signaling in brain tumors.

    Evidence Confocal localization, blocking antibody, overexpression, siRNA, ex vivo brain slice invasion assay in glioma cells

    PMID:15126357

    Open questions at the time
    • Direct kinase substrates mediating lamellipodia formation were not identified
  5. 2005 Medium

    Identifying R-Ras as a proximal signaling partner: EphB2 activation recruits and phosphorylates R-Ras, linking EphB2 to MAPK suppression and explaining the anti-proliferative arm of EphB2 signaling in glioma.

    Evidence Co-IP, siRNA knockdown of R-Ras, phosphorylation analysis in glioma cells

    PMID:16049340

    Open questions at the time
    • R-Ras involvement not validated in non-glioma systems
    • Whether R-Ras mediates anti-proliferative signaling in normal tissue is unknown
  6. 2007 High

    Defining EphB2 proteolytic processing: two distinct cleavage pathways were delineated—ligand-induced endosomal processing via γ-secretase and calcium/NMDA-induced surface cleavage via ADAM10—revealing how EphB2 signaling is terminated or converted to nuclear signaling via ICD release.

    Evidence Pharmacological inhibitors of metalloproteinase, γ-secretase, and endocytosis; cleavage site mapping; ubiquitination assays

    PMID:17428795

    Open questions at the time
    • Transcriptional targets of the released EphB2 intracellular domain are unknown
    • Whether familial AD presenilin mutations affect EphB2 processing in vivo was not demonstrated
  7. 2009 High

    Genetically dissecting kinase-dependent vs. kinase-independent pathways in vivo: kinase-dead knock-in mice revealed that EphB2 controls cell positioning via PI3K (kinase-independent) and proliferation via Abl–cyclin D1 (kinase-dependent), and that cyclin D1 regulation uncouples during colorectal adenoma-to-carcinoma transition.

    Evidence Kinase-dead mutant knock-in mice, PI3K inhibitors, genetic epistasis, human colorectal tumor analysis

    PMID:19914164

    Open questions at the time
    • How PI3K is recruited in the absence of kinase activity is not structurally resolved
    • Whether the Abl–cyclin D1 axis operates in non-intestinal tissues is untested
  8. 2011 High

    Establishing EphB2 forward signaling in brain morphogenesis: ephrin-B1–EphB2 forward kinase signaling directs migration of neural progenitors and regulates Reelin expression during dentate gyrus development.

    Evidence Intracellular truncation and point mutant knock-in mice, ephrin-B1 KO, Reelin and nestin immunoreactivity

    PMID:21832177

    Open questions at the time
    • Molecular link between EphB2 kinase activity and Reelin transcriptional regulation is not defined
  9. 2012 Medium

    Identifying FAK as a direct EphB2 effector controlling the proliferation/migration switch in glioblastoma stem cells.

    Evidence Co-IP of EphB2–FAK, gain/loss-of-function, dual-fluorescent xenograft

    PMID:22310282

    Open questions at the time
    • Whether FAK interaction requires EphB2 kinase activity or only scaffolding was not resolved
    • Reciprocal co-IP and endogenous validation limited
  10. 2013 Medium

    Linking EphB2 kinase activity to MMP-dependent invasion and dual regulation of apoptosis and autophagy in breast cancer cells.

    Evidence Kinase-dead mutant, DOX-inducible EphB2 restoration, MMP2/MMP9 neutralizing antibodies, caspase and autophagy markers

    PMID:24211352

    Open questions at the time
    • Direct ubiquitin/autophagy pathway connections were not biochemically defined in this system
  11. 2014 Medium

    Extending EphB2 function to hemostasis: EphB2 cytoplasmic domain regulates thrombus formation and clot retraction through both contact-dependent and contact-independent mechanisms in platelets.

    Evidence EphB2 cytoplasmic domain-truncated mice, platelet activation assays, thrombus formation models

    PMID:25370417

    Open questions at the time
    • Platelet-intrinsic signaling partners downstream of EphB2 cytoplasmic domain are not identified
    • Contact-independent signaling mechanism is unexplained
  12. 2015 High

    Establishing EphB2 as a driver of hepatic fibrosis by promoting hepatic stellate cell activation and myofibroblast differentiation, validated across two independent fibrosis models.

    Evidence EphB2 KO mice in CCl4 and malaria liver fibrosis models, HSC isolation and differentiation assays

    PMID:25784101

    Open questions at the time
    • Which ephrin ligand activates EphB2 on HSCs in vivo is not established
    • Downstream signaling cascade in HSCs is not mapped
  13. 2017 Medium

    Defining a mitochondrial protection pathway: EphB2 induces Sirt3 via c-Src/Nrf-2 transcription, and Sirt3 deacetylates MnSOD-K68 to reduce mitochondrial ROS, linking EphB2 to cellular senescence resistance.

    Evidence EphB2 knockdown/activation, Nrf-2 nuclear translocation, Sirt3 overexpression/knockdown, MnSOD acetylation assays in MSCs

    PMID:28687409

    Open questions at the time
    • Pathway validated only in mesenchymal stem cells
    • Whether EphB2-Sirt3 axis operates in neurons or hepatocytes is unknown
  14. 2017 Medium

    Demonstrating that nanoscale ligand geometry controls EphB2 oligomerization kinetics, showing that receptor clustering is tuned by spatial organization rather than ligand concentration alone.

    Evidence Diblock copolymer nanopatterning of ephrin-B1, Number and Brightness fluorescence imaging

    PMID:29243484

    Open questions at the time
    • Whether nanoscale ligand geometry differentially activates downstream signaling branches is untested
  15. 2018 High

    Demonstrating that EphB2 kinase activity is required for fear memory consolidation via CREB activation in the lateral amygdala, using optogenetic precision to temporally define the signaling window.

    Evidence Optogenetic optoEphB2 activation, kinase-dead control, CREB phosphorylation, behavioral fear conditioning, EphB2lacZ/lacZ mice

    PMID:29768201

    Open questions at the time
    • Intermediate kinases between EphB2 and CREB phosphorylation in amygdala are not identified
  16. 2020 High

    Revealing ubiquitin-dependent autophagy initiation: RNF186 ubiquitinates EphB2 at K892 upon ephrin-B1 stimulation, enabling LC3B recruitment and autophagosome formation; disruption of this pathway worsens colitis in vivo.

    Evidence Ubiquitination assays, K892R mutagenesis, LC3B co-IP, RNF186/EPHB2 KO mice in DSS colitis model

    PMID:33280498

    Open questions at the time
    • Whether K892 ubiquitination is K63-linked or another chain type is not specified
    • Whether other E3 ligases can compensate for RNF186 is unknown
  17. 2021 High

    Establishing an EphB2–SRC/AKT/β-catenin positive feedback loop in hepatocellular carcinoma: TCF1 transcribes EPHB2, which activates SRC/AKT/GSK3β to stabilize β-catenin, driving stemness and sorafenib resistance.

    Evidence EPHB2 KO, promoter assays, patient-derived xenografts, AAV-shEPHB2, pathway inhibitors

    PMID:33903122

    Open questions at the time
    • Whether the feedback loop operates in normal hepatocytes or is cancer-specific is not determined
  18. 2023 High

    Placing EphB2 downstream of Notch signaling in hepatocytes: EphB2 mediates cell-autonomous inflammatory signaling sufficient to drive NASH pathology, identifying a new non-kinase tissue context for EphB2 function.

    Evidence Single-nucleus multi-omics, hepatocyte-specific Ephb2 knockdown in mouse NASH model

    PMID:36753562

    Open questions at the time
    • Whether EphB2 acts through kinase-dependent or -independent mechanisms in NASH hepatocytes is not resolved
    • The direct downstream inflammatory mediators of EphB2 in hepatocytes are not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for PI3K recruitment in the kinase-independent pathway, the nuclear targets of the γ-secretase-released EphB2 intracellular domain, and which ephrin ligands activate EphB2 in specific disease contexts such as hepatic fibrosis and NASH.
  • No structural data for kinase-independent PI3K engagement
  • ICD transcriptional targets undefined
  • Ligand identity in hepatic/renal fibrosis contexts unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-112316 Neuronal System 5 R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 2 R-HSA-1266738 Developmental Biology 1 R-HSA-5357801 Programmed Cell Death 1
Partners
EFNA5EFNB1EFNB2FAKGRIN1RNF186RRASSRC

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 EphB2 and ephrin-A5 bind each other with high affinity (cross-class interaction), leading to receptor clustering, autophosphorylation, and downstream signaling including growth cone collapse and neurite retraction. X-ray crystallography revealed the ephrin-A5–EphB2 complex is a heterodimer, architecturally distinct from the tetrameric EphB2–ephrin-B2 structure. X-ray crystallography, cell-based receptor clustering/autophosphorylation assays, neurite retraction assay, binding affinity measurements Nature neuroscience High 15107857
1998 Phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region is required for complex formation with the SH2 domain of Src kinase; tyrosines 605 and 611 are important for EphB2 kinase activity. Autophosphorylated EphB2 associates with Src, and EphB2-expressing cells show increased Src tyrosine phosphorylation, suggesting Src as a downstream effector. Yeast two-hybrid, site-directed mutagenesis, co-immunoprecipitation from transfected COS cells, phosphopeptide mapping Oncogene High 9632142
2001 EphB2 regulates NMDA receptor-dependent synaptic function in the mammalian CNS. Mice lacking the entire EphB2 receptor (but not those lacking only the kinase domain) showed reduced LTP and reduced synaptic NMDA current in dentate granule neurons, with diminished synaptically localized NR1 subunit. EphB2 knockout mice (full receptor vs. kinase-domain truncation), electrophysiology (LTP, NMDA currents), immunogold localization of NR1 Neuron High 11754836
2001 EphB2 regulates hippocampal synaptic plasticity in a kinase-independent manner. Mice lacking EphB2 show impaired protein synthesis-dependent LTP and loss of two forms of synaptic depression; a C-terminally truncated EphB2 (lacking the kinase domain) rescues the null phenotype, demonstrating the extracellular/juxtamembrane domain is sufficient. EphB2 knockout mice, targeted truncation knock-in, hippocampal slice electrophysiology Neuron High 11754835
2004 EphB2 is localized to lamellipodia of migrating glioma cells; its phosphorylation (activation) promotes glioma cell migration and invasion, while blocking EphB2 with an antibody inhibits these processes. Forced EphB2 expression in low-expressing U251 cells stimulates migration, invasion and reduces adhesion concomitant with EphB2 tyrosine phosphorylation. Confocal microscopy (localization), blocking antibody, forced overexpression, siRNA knockdown, ex vivo brain slice invasion assay Cancer research High 15126357
2005 EphB2 signals through R-Ras to regulate glioma cell adhesion, proliferation and invasion. Upon EphB2 activation, R-Ras associates with the receptor and becomes phosphorylated; siRNA depletion of R-Ras abrogates EphB2-mediated effects. Anti-proliferative responses to EphB2 correlate with suppressed MAPK activity. Co-immunoprecipitation, siRNA knockdown of R-Ras, ex vivo brain slice invasion, phosphorylation analysis The American journal of pathology Medium 16049340
2007 EphB2 receptor undergoes two distinct processing pathways: (1) ligand (ephrinB)-induced processing requires endocytosis and involves cleavage in endosomes followed by gamma-secretase (presenilin-dependent) cleavage releasing the intracellular domain; (2) calcium influx/NMDA-induced processing occurs at the plasma membrane and requires ADAM10/metalloproteinase activity but not endocytosis. EphrinB stimulation also induces EphB2 ubiquitination. Presenilin-1 familial Alzheimer disease mutations inhibit gamma-secretase cleavage of EphB2. Pharmacological inhibitors (metalloproteinase, gamma-secretase, endocytosis blockers), site-specific cleavage mapping, ubiquitination assays The Journal of biological chemistry High 17428795
2009 EphB2 controls cell proliferation and cell migration through dissociable signaling pathways: kinase-independent, PI3K-mediated pathway controls cell positioning/migration; EphB2 tyrosine kinase activity controls proliferation via an Abl–cyclin D1 pathway. Cyclin D1 regulation becomes uncoupled from EphB signaling during adenoma-to-carcinoma progression. Kinase-dead mutant knock-in mice, PI3K inhibitors, genetic epistasis, tumor progression analysis in human colorectal samples Cell High 19914164
2007 Azurin (a cupredoxin) binds to the EphB2 receptor with high affinity via a domain structurally similar to the G-H loop of ephrinB2, interfering with ephrinB2-induced autophosphorylation of EphB2 tyrosine residues and inhibiting cancer cell growth in EphB2-expressing cells but not in cells lacking functional EphB2. Binding assays (EphB2-Fc), synthetic peptide competition, autophosphorylation assays, cell viability in EphB2-positive vs. negative cell lines Biochemistry Medium 17249693
2012 EphB2 controls a proliferation/migration dichotomy in glioblastoma stem-like cells through interaction with focal adhesion kinase (FAK): EphB2 expression co-associates with and activates FAK, which facilitates focal adhesion formation, cytoskeletal changes and cell migration while inhibiting proliferation. Co-immunoprecipitation (EphB2-FAK), gain- and loss-of-function (overexpression, siRNA), dual-fluorescent xenograft model, in vitro migration/invasion assays Oncogene Medium 22310282
2011 EphB2 tyrosine kinase catalytic activity is required for embryonic/postnatal development of the lateral suprapyramidal blade of the dentate gyrus. Ephrin-B1 acts as the ligand stimulating EphB2 forward signaling to direct migration of nestin-positive neural progenitors; disruption of EphB2 forward signaling reduces Reelin expression in a key compartment above the developing lateral suprapyramidal blade. Intracellular truncation and point mutant knock-in mice, genetic loss of ephrin-B1, immunoreactivity for Reelin and nestin, histological analysis The Journal of neuroscience High 21832177
2016 miR-204 directly targets EphB2 mRNA in hippocampal neurons; upregulation of miR-204 with aging suppresses EphB2 protein expression, reducing surface and total NR1 (NMDA receptor subunit) expression, contributing to age-associated decline in synaptic plasticity. miR-204 mimic transfection, luciferase reporter (direct target validation), western blot, surface NR1 quantification Aging cell Medium 26799631
2018 EphB2 forward signaling (kinase activity) during fear conditioning enhances long-term memory consolidation; photoactivation of optoEphB2 in lateral amygdala during learning activates CREB. A kinase-dead optoEphB2 fails to enhance memory or activate CREB. EphB2lacZ/lacZ mice lacking forward signaling show impaired long-term fear memory. Optogenetic activation (optoEphB2), kinase-dead mutant control, CREB phosphorylation assay, behavioral fear conditioning Cell reports High 29768201
2020 RNF186, an E3 ubiquitin ligase, ubiquitinates EPHB2 at Lys892 upon ephrin-B1 (EFNB1) stimulation, leading to EPHB2-dependent recruitment of MAP1LC3B and induction of autophagy in colonic epithelial cells. Mutation of Lys892 abolishes EPHB2-mediated autophagy. RNF186 and EPHB2 knockout mice show defective autophagy and more severe DSS-induced colitis. Ubiquitination assays, site-directed mutagenesis (K892R), LC3B co-immunoprecipitation, knockout mouse models, DSS colitis model Autophagy High 33280498
2021 EPHB2 drives cancer stemness and sorafenib resistance in hepatocellular carcinoma via the SRC/AKT/GSK3β/β-catenin signaling cascade. TCF1 activates EPHB2 transcription, forming a positive Wnt/β-catenin feedback loop. EPHB2 endogenous knockout attenuates tumor development; rAAV-8-shEPHB2 sensitizes HCC to sorafenib in vivo. EPHB2 knockout, pharmacological pathway inhibitors, promoter activation assay, patient-derived xenografts, AAV-mediated shRNA knockdown, pathway phosphorylation analysis Cancer research High 33903122
2023 EphB2 acts downstream of Notch signaling in hepatocytes and is sufficient to induce cell-autonomous inflammation. Knockdown of Ephb2 in hepatocytes ameliorates inflammation and fibrosis in a mouse NASH model. Single-nucleus transcriptomics/epigenomics, hepatocyte-specific Ephb2 knockdown, mouse NASH model (inflammation and fibrosis readouts) Science translational medicine High 36753562
2015 EphB2 promotes hepatic fibrosis via activation of hepatic stellate cells (HSCs): EphB2 is upregulated and activated in mouse HSCs following CCl4 exposure. EphB2-deficient HSCs show impaired proliferation and sub-optimal differentiation into fibrogenic myofibroblasts; EphB2 KO mice have reduced fibrosis, inflammation, and increased apoptosis in liver. EphB2 knockout mice, two models of hepatic fibrosis (malaria and CCl4), HSC isolation and in vitro differentiation assays, macrophage depletion Hepatology High 25784101
2018 EphB2 receptor tyrosine kinase promotes hepatic fibrogenesis via activation of hepatic stellate cells; EphB2 deficiency attenuates HSC proliferation, myofibroblast differentiation, and fibrosis. EphB2 KO mice show increased cellular apoptosis during fibrosis regression. EphB2 knockout mice, CCl4 model, in vitro HSC activation, fibrosis marker quantification, apoptosis assays Scientific reports Medium 29416088
2021 Loss of EPHB2 in prostate cancer cells increases lipid droplet accumulation by upregulating lipogenic proteins DGAT1, DGAT2, PLIN2 and downregulating lipolytic ATGL and PEDF. DGAT1 inhibition reverses LD accumulation and proliferation caused by EPHB2 loss. EPHB2 knockdown, lipid droplet imaging, western blot of lipid metabolism proteins, DGAT1 inhibitor rescue, cell proliferation assays Laboratory investigation Medium 33824421
2014 EphB2 in platelets regulates thrombus formation and clot retraction both in a contact-dependent (Eph-ephrin ligation between platelets) and contact-independent manner (cytoplasmic domain signaling in isolated platelets without ephrin engagement). EphB2 cytoplasmic domain-truncated mice, platelet activation assays, thrombus formation models, clot retraction assays Blood Medium 25370417
2017 Nanostructured surface-bound ephrinB1 ligands induce EphB2 receptor oligomerization/clustering on cell membranes more efficiently than randomly distributed ligands; nanopatterned ligands required 9-fold lower surface coverage and produced faster clustering kinetics, demonstrating that multivalent ligand presentation tunes receptor activation. Diblock copolymer nanopatterning, Number and Brightness fluorescence technique to track EphB2 oligomeric state in real time Nano letters Medium 29243484
2017 EphB2 activation by ephrin-B2-Fc in cutaneous squamous cell carcinoma cells enhances production of invasion proteinases MMP13 and MMP1 and promotes invasion; EphB2 knockdown suppresses growth, vascularization, proliferation, migration and invasion of cSCC, and downregulates MMP1 and MMP13. siRNA knockdown, ephrin-B2-Fc stimulation, xenograft tumor model, MMP protein expression, gene expression profiling The Journal of investigative dermatology Medium 25789706
2019 EphrinB2/EphB2 promotes myenteric synaptic sprouting and NMDA receptor-mediated synaptic potentiation in IBS, via ERK-MAPK and PI3K-AKT pathways; EphB2 signaling drives persistent colonic hypercontractility and pain hypersensitivity. PI-IBS rat model, ephB2Fc receptor blocker, MK801 NMDA inhibitor, colonic muscle contraction recording, signaling pathway analysis, LMMP culture FASEB journal Medium 31601124
2017 EphB2 signaling induces Sirt3 expression and mitochondrial translocation of Sirt3 via c-Src phosphorylation and Nrf-2-dependent transcription, reducing mitochondrial ROS accumulation. Sirt3 deacetylates MnSOD at Lys68 to enhance its activity, protecting mesenchymal stem cells from senescence. EphB2 knockdown/activation, subcellular fractionation, Nrf-2 nuclear translocation assay, Sirt3 overexpression/knockdown, MnSOD activity and acetylation assays, wound healing model Free radical biology & medicine Medium 28687409
2018 EphB2 inactivation results in depression-like behaviors, memory impairment, and adult hippocampal neurogenesis defects, associated with decreased pCREB and BDNF and increased NR2B expression. NR2B antagonist Ro25-6981 reverses these phenotypes, placing NR2B downstream of EphB2 in behavioral and morphological outcomes. EphB2 knockout mice, behavioral tests (forced swim, tail suspension, Morris water maze, object recognition), NR2B pharmacological antagonism, BrdU neurogenesis assay, western blot Frontiers in pharmacology Medium 30131699
2021 EphB2 receptor is required in kidney for fibrosis development: EphB2 KO mice show significantly reduced renal tubular injury, fibrosis, inflammation and EMT after ischemia-reperfusion injury. EphB2 loss restores expression of 70.9% of fibrosis-associated genes dysregulated by IR injury back to normal. EphB2 knockout mice, renal ischemia-reperfusion model, fibrosis gene expression panel (760 genes), histology, EMT/myofibroblast markers Clinical science Medium 34462781
2013 EphB2 in breast cancer cells promotes apoptosis (via caspase 3/9 activation), induces autophagy (LC3, ATG5, ATG12 markers), and mediates invasion through regulation of MMP2 and MMP9. EphB2-induced invasion is kinase-dependent, as it is blocked by a kinase-dead EphB2 mutant. DOX-inducible EphB2 restoration, siRNA knockdown, kinase-dead mutant, xenograft, MMP2/MMP9 neutralizing antibodies, caspase and autophagy marker analysis Experimental cell research Medium 24211352

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 ERK/MAPK signalling pathway and tumorigenesis. Experimental and therapeutic medicine 1617 32104259
2005 Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nature reviews. Molecular cell biology 865 16227978
2006 ERK implication in cell cycle regulation. Biochimica et biophysica acta 633 17188374
2007 Integrating signals from RTKs to ERK/MAPK. Oncogene 479 17496910
2008 The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. The international journal of biochemistry & cell biology 378 18562239
2004 Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nature neuroscience 374 15107857
1998 Extracellular signal-regulated kinase (ERK) controls immediate early gene induction on corticostriatal stimulation. The Journal of neuroscience : the official journal of the Society for Neuroscience 283 9786988
2001 The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 264 11754836
2001 Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 249 11754835
1999 Both Erk and p38 kinases are necessary for cytokine gene transcription. American journal of respiratory cell and molecular biology 249 10101008
2006 Role of ERK in cocaine addiction. Trends in neurosciences 233 17084911
2013 Autophagy proteins regulate ERK phosphorylation. Nature communications 224 24240988
2010 ERK in learning and memory: a review of recent research. International journal of molecular sciences 206 20162012
2019 AKT and ERK dual inhibitors: The way forward? Cancer letters 184 31128213
1999 Sp1 phosphorylation by Erk 2 stimulates DNA binding. Biochemical and biophysical research communications 181 9918860
2003 Chronic activation of ERK and neurodegenerative diseases. BioEssays : news and reviews in molecular, cellular and developmental biology 175 14579249
2004 The phosphorylation of EphB2 receptor regulates migration and invasion of human glioma cells. Cancer research 148 15126357
2017 A compendium of ERK targets. FEBS letters 145 28675784
2009 Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell 145 19914164
2017 The Spatiotemporal Limits of Developmental Erk Signaling. Developmental cell 137 28118601
2017 ERK signalling as a regulator of cell motility. Journal of biochemistry 137 28903547
2005 EphB2/R-Ras signaling regulates glioma cell adhesion, growth, and invasion. The American journal of pathology 128 16049340
2021 EPHB2 Activates β-Catenin to Enhance Cancer Stem Cell Properties and Drive Sorafenib Resistance in Hepatocellular Carcinoma. Cancer research 115 33903122
2015 Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes. Cancer cell 114 26267534
2005 Reduced expression of EphB2 that parallels invasion and metastasis in colorectal tumours. Carcinogenesis 107 16272170
2007 Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. The Journal of biological chemistry 104 17428795
2004 Expression of Ephb2 and Ephb4 in breast carcinoma. Pathology oncology research : POR 104 15029258
2021 MAPK /ERK signaling pathway: A potential target for the treatment of intervertebral disc degeneration. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 103 34536759
1998 Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region. Oncogene 99 9632142
2001 ERK pathway positively regulates the expression of Sprouty genes. Biochemical and biophysical research communications 97 11478764
1996 Calcium-dependent activation of Erk-1 and Erk-2 after hypo-osmotic astrocyte swelling. The Biochemical journal 89 8947482
2019 ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine. Molecular cancer therapeutics 83 31744895
2014 Crosstalk between ERK, AKT, and cell survival. Cancer biology & therapy 83 24424114
2003 ERK and RhoA differentially regulate pseudopodia growth and retraction during chemotaxis. The Journal of biological chemistry 83 12571246
2012 EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase. Oncogene 80 22310282
2005 Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. Cancer research 79 16288001
2005 Activation of the extracellular signal regulated kinase (ERK) pathway in human melanoma. Journal of clinical pathology 76 16254105
2016 Artificial dermal templates: A comparative study of NovoSorb™ Biodegradable Temporising Matrix (BTM) and Integra(®) Dermal Regeneration Template (DRT). Burns : journal of the International Society for Burn Injuries 69 27222383
2015 MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition by regulating the co-repressor CtBP. Molecular cell 67 25728771
2013 FGF2 stimulates osteogenic differentiation through ERK induced TAZ expression. Bone 66 24125755
2010 Key role of ERK pathway signaling in lupus. Autoimmunity 66 19961364
2023 MAPK-ERK Pathway. International journal of molecular sciences 64 37298618
2013 Endothelial RAF1/ERK activation regulates arterial morphogenesis. Blood 60 23529931
2013 TNF-α/NF-κB signaling in the CNS: possible connection to EPHB2. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 60 24277482
2015 The RAF-MEK-ERK pathway: targeting ERK to overcome obstacles to effective cancer therapy. Future medicinal chemistry 55 25826360
2007 Cupredoxin-cancer interrelationship: azurin binding with EphB2, interference in EphB2 tyrosine phosphorylation, and inhibition of cancer growth. Biochemistry 55 17249693
2023 Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Science translational medicine 52 36753562
2018 ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 52 29760222
2015 EphB2 Promotes Progression of Cutaneous Squamous Cell Carcinoma. The Journal of investigative dermatology 52 25789706
2013 S-nitrosylation of ERK inhibits ERK phosphorylation and induces apoptosis. Scientific reports 52 23657295
2004 Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis. Laboratory investigation; a journal of technical methods and pathology 52 15448709
2016 miR-204 downregulates EphB2 in aging mouse hippocampal neurons. Aging cell 51 26799631
2020 RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis. Autophagy 49 33280498
2013 Kinetics of gene derepression by ERK signaling. Proceedings of the National Academy of Sciences of the United States of America 47 23733957
2013 Role of the EphB2 receptor in autophagy, apoptosis and invasion in human breast cancer cells. Experimental cell research 45 24211352
2006 GnRH receptor signalling to ERK: kinetics and compartmentalization. Trends in endocrinology and metabolism: TEM 44 16919966
2018 Outstanding questions in developmental ERK signaling. Development (Cambridge, England) 42 30049820
2012 EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion. Neuro-oncology 42 22723427
2015 The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice. Hepatology (Baltimore, Md.) 41 25784101
2013 Extracellular signal-regulated kinase (ERK) activity during sleep consolidates cortical plasticity in vivo. Cerebral cortex (New York, N.Y. : 1991) 41 24047601
2007 BMP suppresses PTEN expression via RAS/ERK signaling. Cancer biology & therapy 41 18059158
2016 Dissecting Therapeutic Resistance to ERK Inhibition. Molecular cancer therapeutics 40 26832798
2020 The road to ERK activation: Do neurons take alternate routes? Cellular signalling 39 31945453
2018 EphB2 receptor tyrosine kinase promotes hepatic fibrogenesis in mice via activation of hepatic stellate cells. Scientific reports 38 29416088
2014 ATGs: Scaffolds for MAPK/ERK signaling. Autophagy 38 24412893
2013 PKC and ERK mediate GH-stimulated lipolysis. Journal of molecular endocrinology 38 23785126
2006 Activation of Akt and Erk pathways in medulloblastoma. Folia neuropathologica 38 17039417
2022 The Roles of EphB2 in Cancer. Frontiers in cell and developmental biology 37 35223830
2022 Regulation of oocyte maturation: Role of conserved ERK signaling. Molecular reproduction and development 36 35908193
2019 Physalin A regulates the Nrf2 pathway through ERK and p38 for induction of detoxifying enzymes. BMC complementary and alternative medicine 36 31072358
2017 miR-204 Regulates Cell Proliferation and Invasion by Targeting EphB2 in Human Cervical Cancer. Oncology research 32 28800788
2012 Extracellular signal-regulated kinase (ERK) regulates cortactin ubiquitination and degradation in lung epithelial cells. The Journal of biological chemistry 32 22514278
2022 Optogenetic actuator - ERK biosensor circuits identify MAPK network nodes that shape ERK dynamics. Molecular systems biology 31 35694820
2014 Increased EphB2 expression predicts cholangiocarcinoma metastasis. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 31 25012246
2003 Intramolecular dephosphorylation of ERK by MKP3. Biochemistry 31 14690430
2021 circMELK promotes glioblastoma multiforme cell tumorigenesis through the miR-593/EphB2 axis. Molecular therapy. Nucleic acids 30 34168916
2018 Lidocaine inhibits melanoma cell proliferation by regulating ERK phosphorylation. Journal of cellular biochemistry 30 30430626
2018 Activation of EphB2 Forward Signaling Enhances Memory Consolidation. Cell reports 29 29768201
2011 EphB2 tyrosine kinase-dependent forward signaling in migration of neuronal progenitors that populate and form a distinct region of the dentate niche. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 21832177
2021 The Role of CaMKII and ERK Signaling in Addiction. International journal of molecular sciences 28 33804804
2019 EphrinB2/ephB2-mediated myenteric synaptic plasticity: mechanisms underlying the persistent muscle hypercontractility and pain in postinfectious IBS. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 31601124
2005 Localizing extracellular signal-regulated kinase (ERK) in pharmacological preconditioning's trigger pathway. Basic research in cardiology 28 16283591
2023 A guide to ERK dynamics, part 2: downstream decoding. The Biochemical journal 27 38038975
2017 EphB2 signaling-mediated Sirt3 expression reduces MSC senescence by maintaining mitochondrial ROS homeostasis. Free radical biology & medicine 27 28687409
2016 Regulation of Numb isoform expression by activated ERK signaling. Oncogene 27 27041567
2015 BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia 27 26050649
2023 Emerging roles and mechanisms of ERK pathway mechanosensing. Cellular and molecular life sciences : CMLS 26 37947896
2018 Activation of the SphK1/ERK/p-ERK pathway promotes autophagy in colon cancer cells. Oncology letters 26 29928348
2018 EphB2 Deficiency Induces Depression-Like Behaviors and Memory Impairment: Involvement of NMDA 2B Receptor Dependent Signaling. Frontiers in pharmacology 26 30131699
2023 An improved Erk biosensor detects oscillatory Erk dynamics driven by mitotic erasure during early development. Developmental cell 25 37714159
2021 Loss of ephrin B2 receptor (EPHB2) sets lipid rheostat by regulating proteins DGAT1 and ATGL inducing lipid droplet storage in prostate cancer cells. Laboratory investigation; a journal of technical methods and pathology 25 33824421
2021 Key role for EphB2 receptor in kidney fibrosis. Clinical science (London, England : 1979) 25 34462781
2017 Convergence of BMI1 and CHD7 on ERK Signaling in Medulloblastoma. Cell reports 25 29212025
2016 EPH/ephrin profile and EPHB2 expression predicts patient survival in breast cancer. Oncotarget 25 26870995
2017 Nanopatterns of Surface-Bound EphrinB1 Produce Multivalent Ligand-Receptor Interactions That Tune EphB2 Receptor Clustering. Nano letters 24 29243484
2001 Association among EPHB2, TrkA, and MYCN expression in low-stage neuroblastomas. Medical and pediatric oncology 24 11464911
2018 ERK inhibitor JSI287 alleviates imiquimod-induced mice skin lesions by ERK/IL-17 signaling pathway. International immunopharmacology 23 30481683
2017 The Nuclear Translocation of ERK. Methods in molecular biology (Clifton, N.J.) 23 27924567
2014 EphB2 regulates contact-dependent and contact-independent signaling to control platelet function. Blood 23 25370417
2019 Ancestral reconstruction reveals mechanisms of ERK regulatory evolution. eLife 22 31407663