Affinage

ERBB4

Receptor tyrosine-protein kinase erbB-4 · UniProt Q15303

Length
1308 aa
Mass
146.8 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 37 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

ERBB4/HER4 is a neuregulin-activated receptor tyrosine kinase that couples extracellular EGF-family ligand binding to both canonical cytoplasmic signaling and a distinctive nuclear/mitochondrial signaling mode, with essential roles in cardiac and neural development, GABAergic circuit function, and tissue homeostasis (PMID:7902537, PMID:7477376). Ligand binding drives formation of an asymmetric kinase-domain dimer structurally identical to that of activated EGFR, which is required for kinase activation and autophosphorylation (PMID:18334220, PMID:20022944), and cryo-EM of near-full-length HER4 homodimers and HER2/HER4 heterodimers shows that glycan modifications and interface dynamics distinguish these dimer states (PMID:38498590). Activated ERBB4 engages the Shc-MAPK pathway and, in an isoform-dependent manner, PI3K-Akt: the CYT-1 cytoplasmic isoform activates PI3K-Akt and supports survival and chemotaxis whereas CYT-2 does not (PMID:7759543, PMID:11343971). Uniquely among ErbB receptors, the JM-a isoform undergoes sequential TACE/ADAM17-mediated ectodomain shedding followed by presenilin/γ-secretase cleavage to release a soluble intracellular domain (4ICD); blocking γ-secretase cleavage abolishes nuclear translocation, STAT5A-driven transcription, mitochondrial accumulation, and apoptosis (PMID:10744726, PMID:15746097). In the nucleus 4ICD potentiates STAT5A activity through direct serine phosphorylation events and coactivates ERα at estrogen-responsive promoters, forming an autocrine loop with estrogen-induced ERBB4 (PMID:15863494, PMID:16912174), while at mitochondria 4ICD acts as a BH3-only protein requiring an intact BH3 domain and BAK to trigger cytochrome c release and apoptosis, an activity suppressed by BCL-2 (PMID:15746097, PMID:18676864). In the nervous system ErbB4 mediates NRG1 signaling to control excitatory and inhibitory synapses and GABAergic interneuron function, governing hippocampal-prefrontal synchrony and attention (PMID:17521571, PMID:29628188); it also promotes inhibitory synapse formation through a kinase-independent trans-adhesive interaction with Slitrk3 via its extracellular RLD domain (PMID:34226493). Timeline evidence links ERBB4 mutations that reduce NRG1-stimulated autophosphorylation to amyotrophic lateral sclerosis (ALS19) (PMID:24119685).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1993 High

    Established that HER4/ErbB4 is a functional receptor whose intrinsic kinase is directly activated by heregulin/neuregulin, defining the ligand-receptor relationship at the heart of the pathway.

    Evidence Recombinant heregulin binding and receptor phosphorylation assays in cell lines expressing recombinant receptors

    PMID:7902537

    Open questions at the time
    • Did not resolve downstream effectors
    • Did not address receptor dimerization or activation mechanism
  2. 1995 High

    Demonstrated that ErbB4 is an essential in vivo neuregulin receptor, anchoring its developmental requirement in cardiac trabeculation and CNS axon guidance.

    Evidence ErbB4 knockout mice with histological developmental phenotyping

    PMID:7477376

    Open questions at the time
    • Embryonic lethality limits analysis of later/adult roles
    • Cell-autonomous vs. systemic contributions not separated
  3. 1995 Medium

    Identified Shc as an immediate downstream adaptor, beginning the mapping of ErbB4's cytoplasmic signaling outputs.

    Evidence Heregulin-Fc stimulation with Shc immunoprecipitation and anti-phosphotyrosine blotting

    PMID:7759543

    Open questions at the time
    • Did not connect Shc to a specific phenotype
    • Single readout of phosphorylation
  4. 2000 High

    Resolved the protease and isoform determinants of ectodomain shedding, showing TACE/ADAM17 cleaves only the JM-a isoform — the prerequisite for regulated intracellular signaling.

    Evidence TACE-null cells with re-expression rescue and JM-a/JM-b isoform-swap experiments

    PMID:10744726

    Open questions at the time
    • Did not address the second (gamma-secretase) cleavage step
    • Physiological triggers of shedding beyond phorbol ester/pervanadate not defined
  5. 2000 Medium

    Defined functional divergence of the cytoplasmic CYT-1/CYT-2 isoforms, establishing PI3K-Akt coupling as a CYT-1-specific output for survival and chemotaxis.

    Evidence Isoform expression with PI3K/Akt/MAPK signaling and functional survival, chemotaxis, proliferation assays

    PMID:11343971

    Open questions at the time
    • Review-summarized original data
    • Molecular basis of differential PI3K recruitment not mapped
  6. 2005 High

    Showed presenilin/gamma-secretase cleavage is required to liberate 4ICD, linking proteolysis to nuclear translocation, STAT5A transcription, and mitochondrial apoptosis through a single non-cleavable mutant.

    Evidence V673I cleavage-resistant mutant, gamma-secretase inhibitors, nuclear fractionation, STAT5A reporter and apoptosis assays

    PMID:15746097

    Open questions at the time
    • Did not define nuclear import machinery
    • Mitochondrial targeting determinants left open
  7. 2005 High

    Defined the molecular basis of ERBB4-STAT5A coactivation via specific serine phosphorylations required for STAT5A activation and stable interaction, validated in ERBB4-null mammary tissue.

    Evidence Mass spectrometry site mapping, STAT5A serine-to-alanine mutagenesis, co-IP, and ERBB4-null mammary immunohistochemistry

    PMID:15863494

    Open questions at the time
    • Whether full-length receptor or 4ICD performs the phosphorylation in vivo not fully resolved
    • Genome-wide STAT5A target scope not defined
  8. 2006 High

    Established 4ICD as a BH3-only proapoptotic effector, identifying BAK (not BAX) dependence and BCL-2 antagonism as the mitochondrial death mechanism.

    Evidence Subcellular fractionation, BH3 mutagenesis, BAK/BAX siRNA, cytochrome c release, BCL-2 overexpression, and xenografts

    PMID:16778220

    Open questions at the time
    • Direct 4ICD-BAK binding stoichiometry not determined
    • Conditions favoring apoptotic vs. transcriptional 4ICD fate unclear
  9. 2006 High

    Linked 4ICD to estrogen signaling as an ERalpha coactivator at selected promoters, with ERBB4 itself estrogen-inducible, establishing an autocrine transcriptional loop.

    Evidence Reciprocal co-IP, ChIP, siRNA knockdown, and transcriptional reporter assays

    PMID:16912174

    Open questions at the time
    • Basis of promoter selectivity (PgR/SDF-1 vs pS2) not explained
    • Interplay with STAT5A coactivation not addressed
  10. 2006 High

    Connected ErbB4 to a tumor-suppressive cell-cycle arrest via JNK-driven BRCA1 induction, showing growth-inhibitory as well as proliferative outputs.

    Evidence Heregulin stimulation, JNK/ERK inhibition, BRCA1 siRNA, isogenic BRCA1+/- cells, and cell cycle analysis

    PMID:16914727

    Open questions at the time
    • How JNK is selectively engaged by ErbB4 not defined
    • Reconciliation with proliferative signaling context-dependent
  11. 2008 High

    Provided the structural basis of ErbB4 kinase activation, showing the active kinase forms an asymmetric dimer identical to EGFR and that lapatinib traps an inactive conformation.

    Evidence X-ray crystallography of active and lapatinib-bound kinase domains plus mutagenesis in Ba/F3 cells

    PMID:18334220

    Open questions at the time
    • Full-length ectodomain-mediated dimerization not captured
    • Heterodimer-specific activation not addressed structurally
  12. 2009 High

    Quantified cooperative asymmetric-dimer activation in vitro and defined C-lobe sequence determinants governing which partner activates Her4, explaining heterodimer selectivity.

    Evidence Reconstituted nickel-liposome kinase assays with Her3 C-lobe mutagenesis

    PMID:20022944

    Open questions at the time
    • In vitro liposome system may not capture full-length cellular regulation
    • Physiological partner hierarchy in cells not ranked

Open questions

Synthesis pass · forward-looking unresolved questions
  • Multiple isoform-, mutation-, and context-specific signaling outputs (CYT-1/CYT-2 nuclear potency, PDGFRA/AP-2 and SREBP-2 transcriptional programs, KAP1/PTPN21 regulation, cancer-activating mutations, neuronal NRG/ErbB4 circuit and disease links in ALS and Alzheimer's, and cardioprotective small-molecule agonism) extend the model but the rules that select between cytoplasmic, nuclear-transcriptional, and mitochondrial-apoptotic ErbB4 fates in a given cell remain unresolved.
  • No unifying determinant of 4ICD trafficking fate
  • Direct S100A4-ErbB4 interaction not resolved (Low-confidence)
  • Disease mechanisms beyond receptor-level readouts incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060089 molecular transducer activity 3 GO:0140110 transcription regulator activity 3 GO:0140313 molecular sequestering activity 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 1
Partners
BAK1BCL2ESR1NRG1PTPN21SHC1SLITRK3STAT5A

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Heregulin (neuregulin) is a specific ligand for HER4/ErbB4 that directly activates HER4's intrinsic tyrosine kinase activity and induces tyrosine phosphorylation; heregulin fails to phosphorylate HER2 in the absence of HER4, indicating HER4 is required for heregulin signal transduction. Ligand binding assays and receptor phosphorylation studies using recombinant heregulin on cell lines expressing recombinant receptors Nature High 7902537
1995 ErbB4 is an essential in vivo receptor for neuregulins in cardiac muscle differentiation (myocardial trabeculation) and axon guidance in the CNS hindbrain; ErbB4-null mice die mid-embryogenesis from failed ventricular trabeculation. ErbB4 knockout mice (gene targeting), histological and developmental phenotype analysis Nature High 7477376
1995 Heregulin-induced HER4 activation leads to tyrosine phosphorylation of Shc adaptor proteins, implicating Shc as a downstream signaling molecule in HER4-mediated signal transduction. Heregulin-Fc fusion protein stimulation of HER4-expressing cells, immunoprecipitation and anti-phosphotyrosine Western blot of Shc The Journal of biological chemistry Medium 7759543
1998 ErbB4 homodimerization at high expression levels is required for neuregulin-stimulated, IL-3-independent cell proliferation; low ErbB4 expression allows neuregulin-induced phosphorylation but is insufficient to couple activated ErbB4 to mitogenic cellular signaling. Hammerhead ribozyme-mediated ErbB4 knockdown in 32D/ErbB4 cells, proliferation assays, receptor phosphorylation analysis Cancer research Medium 9699674
2000 TACE (tumor necrosis factor-alpha-converting enzyme/ADAM17) is the metalloprotease required for regulated ectodomain shedding of the HER4 JM-a isoform; the juxtamembrane sequence specific to JM-a confers susceptibility to TACE-mediated cleavage, while JM-b is resistant. TACE-deficient cells with TACE re-expression, phorbol ester and pervanadate stimulation, JM-a/JM-b isoform swap experiments The Journal of biological chemistry High 10744726
2000 The two cytoplasmic ErbB4 isoforms (CYT-1 and CYT-2) differ in signaling: both couple to the Shc-MAPK pathway, but only CYT-1 activates PI3K-Akt signaling; CYT-2 isoform is defective in stimulating cellular survival and chemotaxis, while both can stimulate proliferation. Isoform expression in cells, signaling pathway analysis (PI3K, Akt, MAPK), functional assays (survival, chemotaxis, proliferation) Trends in cardiovascular medicine Medium 11343971
2005 Presenilin-dependent gamma-secretase processing of ErbB4 is required to release the 4ICD intracellular domain; the gamma-secretase-resistant transmembrane mutant ERBB4-V673I retains normal cell-surface signaling but fails to translocate to the nucleus, cannot activate STAT5A-driven beta-casein promoter, and fails to accumulate in mitochondria or induce apoptosis. Site-directed mutagenesis (V673I), gamma-secretase inhibitors, nuclear fractionation, STAT5A transcriptional reporter assay, apoptosis assays The Journal of biological chemistry High 15746097
2005 ERBB4 potentiates STAT5A transcriptional activity through phosphorylation of STAT5A at Ser-127/Ser-128 (required for subsequent Tyr-694 phosphorylation and DNA binding) and Ser-779 (required for stable interaction with ERBB4 and gene activation); ERBB4 expression is required in vivo for STAT5A Ser-779 phosphorylation in mammary gland. Mass spectrometry identification of phosphorylation sites, serine-to-alanine mutagenesis of STAT5A, co-IP, mammary gland immunohistochemistry from ERBB4-null mice The Journal of biological chemistry High 15863494
2006 Ligand-activated ERBB4 undergoes proteolytic processing to release 4ICD, which accumulates in mitochondria and promotes cytochrome c efflux; 4ICD functions as a BH3-only protein requiring an intact BH3 domain and BAK (not BAX) to initiate mitochondrial apoptosis; BCL-2 interaction suppresses 4ICD-induced apoptosis. Ligand stimulation, subcellular fractionation, BH3 domain mutagenesis, BCL-2 overexpression, BAK/BAX siRNA knockdown, cytochrome c release assay, xenograft model Cancer research High 16778220
2006 Estrogen promotes association between estrogen receptor alpha (ERα) and ERBB4; the proteolytically processed 4ICD translocates to the nucleus in a ligand-bound ER-dependent manner and the nuclear ER/4ICD complex selectively coactivates estrogen-inducible promoters (PgR, SDF-1 but not pS2); ERBB4 is itself an estrogen-inducible gene, establishing an autocrine loop. Co-immunoprecipitation, nuclear translocation assay, chromatin immunoprecipitation, siRNA knockdown, transcriptional reporter assays, cell proliferation assay Cancer research High 16912174
2006 An activating transmembrane mutation (I658E) in ERBB4 increases receptor tyrosine phosphorylation ~5-fold, enhances nuclear translocation and STAT5A-driven beta-casein promoter activation, and potentiates proapoptotic function in multiple cancer cell lines while untransformed cells are resistant. Site-directed mutagenesis, tyrosine phosphorylation assay, nuclear fractionation, STAT5A transcriptional reporter, apoptosis assays across multiple cell lines Oncogene Medium 16832345
2006 Heregulin/HER4-induced growth inhibition and G2/M delay in breast cancer cells requires BRCA1 induction via JNK signaling; HER4 activates JNK to upregulate BRCA1 expression independent of HER2 and cell cycle phase; BRCA1 knockdown abolishes HER4-mediated mitotic delay. Heregulin stimulation, pharmacological JNK/ERK inhibition, siRNA BRCA1 knockdown, isogenic BRCA1+/- mouse mammary epithelial cells, cell cycle analysis Molecular and cellular biology High 16914727
2007 The CYT-2 ErbB4 ICD (ICD2) accumulates in the nucleus to a significantly greater extent than CYT-1 ICD (ICD1); ICD2 shows higher tyrosine phosphorylation and greater in vitro kinase activity than ICD1; kinase-dead ICD2 K751R mutation blocks tyrosine phosphorylation and significantly reduces nuclear translocation; ICD2 is more efficient than ICD1 in promoting STAT5 target gene beta-casein transcription. Confocal microscopy, nuclear fractionation, in vitro kinase assay, site-directed mutagenesis (K751R), STAT5 transcriptional reporter Oncogene High 17486069
2007 ErbB4, as a postsynaptic target of NRG1, is recruited into excitatory synapses by synaptic activity; overexpressed ErbB4 selectively enhances AMPA synaptic currents and increases dendritic spine size; preventing NRG1/ErbB4 signaling destabilizes synaptic AMPA receptors and causes loss of synaptic NMDA currents and spines. Electrophysiology (patch clamp), ErbB4 overexpression and dominant negative, live imaging, spine morphology analysis in hippocampal neurons Neuron High 17521571
2008 Crystal structures of the ErbB4 kinase domain in active and lapatinib-inhibited forms reveal that active ErbB4 kinase adopts an asymmetric dimer conformation identical to that of activated EGFR/ErbB1; mutagenesis of intact ErbB4 in Ba/F3 cells confirms the functional importance of this asymmetric dimer for ErbB4 activation; lapatinib binds an inactive kinase conformation. X-ray crystallography, site-directed mutagenesis, functional kinase activity assays in Ba/F3 cells Structure High 18334220
2008 4ICD functions as an ERα coactivator and, upon tamoxifen treatment, the ERα-4ICD interaction is disrupted while 4ICD accumulates in mitochondria as a proapoptotic BH3-only protein; BAK activation (independent of BAX) and BCL-2 inhibition of tamoxifen apoptosis support 4ICD involvement; HER4 with mutated BH3 domain fails to restore tamoxifen sensitivity in xenograft model. Co-immunoprecipitation, siRNA knockdown, tamoxifen resistance models, BH3 domain mutagenesis, xenograft experiments, apoptosis assays Cancer research High 18676864
2009 Her4 kinase domain is activated ~40-fold upon nickel-liposome-mediated dimerization in a concentration-dependent, sigmoidal (cooperative) manner consistent with asymmetric dimer activation; Her3 activates Her2/neu but is a poor activator of Her4; mutation of Her3 C-lobe residues (952)ENI(954) to Her4-corresponding sequence enhances Her3-mediated Her4 activation, demonstrating sequence-specific heterodimerization requirements. Reconstituted in vitro kinase assay with nickel-chelating lipid-liposomes, autophosphorylation assay, site-directed mutagenesis of Her3 The Journal of biological chemistry High 20022944
2010 ErbB4 JM-a isoform promotes enhanced autophosphorylation and cell survival via release of soluble ICD that associates with transcription factor AP-2 to promote PDGFRA transcription; JM-b isoform cells undergo starvation-induced death; PDGFR-α and AP-2 are required for JM-a survival; cells expressing JM-b are rescued by PDGF-BB, identifying PDGFRA as an ErbB4 isoform-specific target gene. ErbB4 isoform expression in fibroblasts, PDGFRA expression analysis, AP-2 co-immunoprecipitation, pharmacological PDGFR-α targeting, rescue experiments with PDGF-BB Molecular biology of the cell Medium 20943952
2010 KRAB-associated protein 1 (Kap1) binds to multiple ErbB4 isoforms independently of ErbB4 kinase activity and is not an ErbB4 substrate; Kap1 reduces ERBB4 transcription; ErbB4 upregulation and MDM2 suppression jointly accelerate p21(CIP1) accumulation in response to DNA damage. Proteomic screen for ErbB4 ICD interactors, Co-IP, transcriptional analysis, DNA damage response assays Molecular cancer research Medium 20858735
2010 ErbB4 promotes COX-2 expression in colon epithelial cells by increasing COX-2 mRNA stability through a Src- and PI3K-dependent mechanism; ErbB4 transactivates EGFR upon heregulin stimulation via heterodimerization, and COX-2 inhibition reverses ErbB4-mediated cell survival and soft-agar colony formation. ErbB4 overexpression and siRNA knockdown, mRNA stability assay, pharmacological inhibition of Src/PI3K/COX-2, EGFR phosphorylation assay, anchorage-independent growth assay Laboratory investigation Medium 20585313
2013 ErbB4 associates with GABAA receptor α1 subunit (GABAR α1) in hippocampal interneurons; a NRG1-mediated ErbB4 signaling pathway, independent of its tyrosine kinase activity, reduces postsynaptic GABAA receptor currents on inhibitory interneurons via clathrin-mediated endocytosis and protein kinase C; ErbB4-null mice have diminished cortical GABAR α1 expression. Unbiased proteomics, electrophysiology, Co-immunoprecipitation, pharmacological inhibition of endocytosis/PKC, immunohistochemistry, ErbB4-null mice PNAS High 24218551
2013 ALS19-associated ERBB4 mutations (p.Arg927Gln in kinase domain; p.Arg1275Trp in C-terminal domain) reduce autophosphorylation of ErbB4 upon NRG-1 stimulation, establishing that loss of neuregulin-ErbB4 signaling underlies ALS pathogenesis. Functional analysis of ERBB4 mutants: ErbB4 autophosphorylation assay upon NRG-1 stimulation, comparison of wild-type vs. mutant receptor activity American Journal of Human Genetics Medium 24119685
2015 ERBB4 activates the SREBP-2 cholesterol biosynthetic pathway via PI3K and mTORC1/2 (but not AKT or mTORC1 alone) signaling downstream; NRG1-activated ERBB4 ICD induces SREBP-2 target genes (HMGCR, HMGCS1, LDLR) to increase LDL uptake and cholesterol biosynthesis; SREBP site 1 protease inhibition or pan-ERBB inhibition (lapatinib) blocks NRG1-induced cholesterol gene expression. ERBB4 ICD expression in mammary epithelial cells, NRG1 stimulation, pharmacological inhibitors of PI3K/mTOR/AKT/lapatinib/erlotinib, gene expression analysis, LDL uptake assay Science signaling Medium 26535009
2015 Four activating ERBB4 mutations in lung adenocarcinoma (Y285C, D595V, D931Y, K935I) increase basal and ligand-induced ErbB4 phosphorylation, enhance ErbB4 dimerization and trans-activation in both homodimers and ErbB4-ErbB2 heterodimers, and markedly increase proteolytic release of signaling-competent ErbB4 ICD. Mutant ERBB4 expression in NIH 3T3 cells, phosphorylation assays, dimerization assays, structural analysis, ICD release measurement Oncogene Medium 26050618
2017 ErbB4 in pro-inflammatory macrophages localizes to mitochondria; NRG4-induced ErbB4 activation causes mitochondrial membrane potential loss and apoptosis requiring proteases that generate the cleaved ErbB4 ICD, consistent with mitochondrial pathway apoptosis; NRG4/ErbB4 signaling limits colitis by clearing pro-inflammatory macrophages. Immunofluorescence (ErbB4 mitochondrial localization), NRG4 treatment, pharmacological protease inhibition, mitochondrial membrane potential assay, apoptosis assays in murine and human macrophages, DSS colitis model Cell death & disease Medium 28230865
2017 ErbB4 deletion in the liver suppresses p53 expression by inhibiting TP53INP1 expression, establishing an ERBB4-TP53INP1-P53 axis in hepatocellular carcinoma suppression. Liver-specific ErbB4 knockout mice, DEN-induced tumor model, microarray gene expression analysis, real-time PCR validation Carcinogenesis Medium 28334319
2018 ErbB4 promotes inhibitory synapse formation through kinase-independent trans-adhesion: ErbB4 interacts in trans with postsynaptic Slitrk3 via ErbB4's extracellular RLD domain; kinase-dead ErbB4 K751M knock-in mice have normal inhibitory synapse numbers (unlike ErbB4-null mice), confirming kinase-independent mechanism. HEK293T co-culture synapse formation assay, K751M kinase-dead mutant KI mice, ErbB4 RLD domain deletion, Slitrk3 neutralization, GABAergic transmission electrophysiology, immunostaining Translational psychiatry High 34226493
2018 S100A4 neuroprotection depends on ErbB4 expression and ErbB2/Akt signaling downstream of ErbB4; S100A4 and S100A4-derived peptides interact with ErbB4 (as well as ErbB1 and ErbB3) and signal through ErbB receptors to promote neuronal survival. ErbB4 expression-dependent neuroprotection assays, functional ErbB4 blockade, ErbB2/Akt inhibition, binding assays Theranostics Low 30083275
2018 Acute ErbB4 kinase inactivation (chemical genetics) and optogenetic inhibition of ErbB4+ interneurons in the hippocampus reduce GABAergic activity, impair hippocampal-prefrontal synchrony, and diminish top-down attention; ErbB4 inactivation in prefrontal cortex alters attention but not synchrony, establishing hippocampal ErbB4 as specifically required for hippocampal-prefrontal synchronization. Chemical genetic ErbB4 kinase inactivation, optogenetic interneuron inhibition, in vivo LFP recording, attention behavioral assays in ErbB4 mutant mice Neuron High 29628188
2011 TNF transactivates ErbB4 through TACE-dependent release of HB-EGF; MEK (but not Src or p38) is required for this transactivation; TACE inhibition or ErbB4 ligand-binding blockade reverses ErbB4-mediated protection of colonic epithelial cells from TNF-induced apoptosis. Neutralizing antibodies against HB-EGF, pharmacological/genetic TACE inhibition, MEK/Src/p38 inhibitors, apoptosis assays in ErbB4-expressing mouse colon epithelial cells American journal of physiology. Gastrointestinal and liver physiology Medium 21617117
2012 In adult rat ventricular myocytes (ARVM), ErbB4 localizes to the nucleus as a full-length protein (not requiring PKC or gamma-secretase), as only the non-cleavable JM-b isoform is expressed in ARVM; ErbB4 kinase activity is required for doxorubicin-induced p53 and p21 upregulation in cardiac myocytes. Nuclear fractionation, isoform expression analysis, gamma-secretase/PKC inhibitors, ErbB4 siRNA knockdown, doxorubicin DNA damage assay, p53/p21 expression analysis Biochemical and biophysical research communications Medium 22244893
2015 PTPN21 de-phosphorylates ErbB4, leading to upregulation of ErbB4 downstream signaling; phosphatase-dead PTPN21 (C1108S) and kinase-dead ErbB4 (K751R) both impede PTPN21-dependent signaling; PTPN21 promotes NRG3 expression through Elk-1 activation downstream of ErbB4. Biotinylated receptor tracking, immunoprecipitation, PTPN21 and ErbB4 kinase-dead mutants, Elk-1 transcriptional analysis, NRG3 promoter analysis in cortical neurons The international journal of biochemistry & cell biology Medium 25681686
2019 ErbB4 promotes malignant peripheral nerve sheath tumor (MPNST) proliferation and survival via Ras-independent signaling through STAT3, STAT5, and phospholipase-Cγ pathways; ErbB4 ablation reduces Ras-independent kinase cascades while broad-spectrum ErbB inhibitors suppress Ras activation, demonstrating distinct ErbB4-specific signaling. Conditional Erbb4 knockout in MPNST mice, orthotopic xenografts of Erbb4-null cells, antibody kinase arrays (43 candidate kinases), pharmacological inhibition of STAT3/STAT5/PLCγ, proliferation and survival assays Cell communication and signaling Medium 31291965
2021 ErbB4 mediates Aβ-induced neurotoxicity through JNK/tau pathway activation; Aβ activates JNK via ErbB4 (distinct from NRG1β1-ErbB4 signaling), and ErbB4 siRNA knockdown decreases JNK and tau phosphorylation at Ser396/Thr205, Bax expression, and PSD-95/synaptophysin loss. ErbB4 siRNA knockdown, ErbB4 kinase inhibitor (AG1478), PV neuron-specific ErbB4 conditional KO, phosphorylation assays for JNK and tau, Western blot, hAPP-J20 mouse model The Journal of comparative neurology Medium 34212389
2024 Cryo-EM structures of near full-length HER2/HER4 heterodimers and full-length HER4 homodimers bound to NRG1β and BTC reveal: HER2/HER4 heterodimer interface is less dynamic than HER2/EGFR or HER2/HER3; HER4 homodimers exhibit more large-scale dynamics than HER2/HER4 heterodimers; multiple glycan modifications on HER4 ectodomains stabilize HER4 homodimer interfaces over HER2/HER4 heterodimer interfaces. Cryo-EM structure determination of near full-length receptor complexes, structural dynamics analysis, glycan modeling eLife High 38498590
2025 Small-molecule compounds (EF-1 to EF-8) can activate ERBB4 by inducing receptor dimerization; EF-1 reduces cardiomyocyte death and hypertrophy and decreases cardiac fibroblast collagen production in an ERBB4-dependent manner; in vivo, EF-1 inhibits angiotensin-II-induced fibrosis and reduces doxorubicin/MI-induced heart damage, with no effect in Erbb4-null mice. Small-molecule screen (10,240 compounds), ERBB4 dimerization assay, cardiomyocyte and fibroblast cell assays, Erbb4-null mouse model with angiotensin-II, doxorubicin, and MI models Nature communications High 39794341
2023 Peripheral Nrg4 signals via ErbB4 in hypothalamic paraventricular nucleus (PVN) oxytocin neurons; ErbB4 overexpression in PVN protects against obesity while ErbB4 knockdown in oxytocin neurons accelerates obesity; Nrg4-ErbB4 signaling excites oxytocin release, and oxytocin neuron ablation attenuates Nrg4's effect on energy balance. PVN ErbB4 overexpression, oxytocin neuron-specific ErbB4 knockdown, central rNrg4 administration, oxytocin neuron ablation, metabolic phenotyping in DIO mice Advanced science Medium 37060105

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 930 7477376
1993 Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature 471 7902537
2007 The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron 291 17521571
2000 Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4. The Journal of biological chemistry 265 10744726
2004 Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nature neuroscience 205 15543145
2003 ErbB-4: mechanism of action and biology. Experimental cell research 194 12648466
2006 The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer research 173 16778220
2008 Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients. Schizophrenia research 150 18243664
2008 Mechanism of activation and inhibition of the HER4/ErbB4 kinase. Structure (London, England : 1993) 141 18334220
2013 ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19. American journal of human genetics 124 24119685
2006 Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells. Cancer research 123 16912174
2005 Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Clinical cancer research : an official journal of the American Association for Cancer Research 122 15788662
2008 Role of ErbB4 in breast cancer. Journal of mammary gland biology and neoplasia 117 18454307
2000 Erbb4 and its isoforms: selective regulation of growth factor responses by naturally occurring receptor variants. Trends in cardiovascular medicine 115 11343971
2005 Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities. The Journal of biological chemistry 110 15746097
2011 Function of ERBB4 is determined by alternative splicing. Cell cycle (Georgetown, Tex.) 98 21811097
2005 The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histology and histopathology 97 15944951
2020 The role of ErbB4 in cancer. Cellular oncology (Dordrecht, Netherlands) 89 32219702
2008 ErbB4/HER4: role in mammary gland development, differentiation and growth inhibition. Journal of mammary gland biology and neoplasia 83 18437540
2017 ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell death & disease 81 28230865
2015 ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. Carcinogenesis 78 25916654
2006 The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients. British journal of cancer 72 16685269
2004 Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. British journal of cancer 72 15583696
2008 HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer. Journal of mammary gland biology and neoplasia 71 18473151
2020 miR-323a regulates ERBB4 and is involved in depression. Molecular psychiatry 66 33219358
2015 Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells. Cell cycle (Georgetown, Tex.) 66 25590338
2018 Dynamic ErbB4 Activity in Hippocampal-Prefrontal Synchrony and Top-Down Attention in Rodents. Neuron 65 29628188
2009 The upgraded role of HER3 and HER4 receptors in breast cancer. Critical reviews in oncology/hematology 65 19481955
2015 Activating ERBB4 mutations in non-small cell lung cancer. Oncogene 63 26050618
2022 The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein. Pharmacological reviews 60 34987087
2021 A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors. Molecules (Basel, Switzerland) 57 34885957
2007 Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains. Oncogene 55 17486069
2009 Her4 and Her2/neu tyrosine kinase domains dimerize and activate in a reconstituted in vitro system. The Journal of biological chemistry 54 20022944
2008 The HER4/4ICD estrogen receptor coactivator and BH3-only protein is an effector of tamoxifen-induced apoptosis. Cancer research 54 18676864
2010 Cell death or survival promoted by alternative isoforms of ErbB4. Molecular biology of the cell 52 20943952
2017 A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer. Oncotarget 51 29179520
2003 c-erbB-4/HER4: friend or foe? The Journal of pathology 51 12845622
2018 Altered ErbB4 splicing and cortical parvalbumin interneuron dysfunction in schizophrenia and mood disorders. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 46 30120408
2014 High incidence of ErbB3, ErbB4, and MET expression in ovarian cancer. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 45 24901400
2003 The EGF receptor family--multiple roles in proliferation, differentiation, and neoplasia with an emphasis on HER4. Transactions of the American Clinical and Climatological Association 44 12813928
2006 A constitutively active ERBB4/HER4 allele with enhanced transcriptional coactivation and cell-killing activities. Oncogene 43 16832345
2011 ErbB4 modulates tubular cell polarity and lumen diameter during kidney development. Journal of the American Society of Nephrology : JASN 42 22076439
2005 ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events. The Journal of biological chemistry 41 15863494
2018 The S100A4 Protein Signals through the ErbB4 Receptor to Promote Neuronal Survival. Theranostics 40 30083275
2011 Basal-like molecular subtype and HER4 up-regulation and response to neoadjuvant chemotherapy in breast cancer. Oncology reports 40 21769435
2010 Reactivation of epigenetically silenced HER4/ERBB4 results in apoptosis of breast tumor cells. Oncogene 39 20603612
2006 Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1. Molecular and cellular biology 37 16914727
2017 Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 36 28573357
2018 Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner. Oncogene 35 29398709
2015 Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake. Science signaling 35 26535009
2020 The role of endothelial autocrine NRG1/ERBB4 signaling in cardiac remodeling. American journal of physiology. Heart and circulatory physiology 33 32618511
2017 ErbB4 signaling in the prelimbic cortex regulates fear expression. Translational psychiatry 32 28675393
2021 NRG4-ErbB4 signaling represses proinflammatory macrophage activity. American journal of physiology. Gastrointestinal and liver physiology 31 33826403
2014 Expression of the EGF family in gastric cancer: downregulation of HER4 and its activating ligand NRG4. PloS one 31 24728052
2013 ErbB4 reduces synaptic GABAA currents independent of its receptor tyrosine kinase activity. Proceedings of the National Academy of Sciences of the United States of America 30 24218551
2011 Antipsychotic treatment and neuregulin 1-ErbB4 signalling in schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry 30 21513767
1995 HER4 expression correlates with cytotoxicity directed by a heregulin-toxin fusion protein. The Journal of biological chemistry 29 7535774
2017 Increased NRG1-ErbB4 signaling in human symptomatic epilepsy. Scientific reports 28 28273943
2017 ERBB4 acts as a suppressor in the development of hepatocellular carcinoma. Carcinogenesis 28 28334319
2006 HER4 in breast cancer: comparison of antibodies against intra- and extra-cellular domains of HER4. Breast cancer research : BCR 28 16606438
1998 Granulosa cell tumors express erbB4 and are sensitive to the cytotoxic action of heregulin-beta2/PE40. Cancer research 28 9581810
2021 ErbB4 mediates amyloid β-induced neurotoxicity through JNK/tau pathway activation: Implications for Alzheimer's disease. The Journal of comparative neurology 27 34212389
2017 ErbB4 deletion accelerates renal fibrosis following renal injury. American journal of physiology. Renal physiology 27 28724608
1995 HER4 receptor activation and phosphorylation of Shc proteins by recombinant heregulin-Fc fusion proteins. The Journal of biological chemistry 27 7759543
2013 HER4 expression status correlates with improved outcome in both neoadjuvant and adjuvant Trastuzumab treated invasive breast carcinoma. Oncotarget 26 24091566
2010 The ERalpha coactivator, HER4/4ICD, regulates progesterone receptor expression in normal and malignant breast epithelium. Molecular cancer 26 20550710
2003 ErbB4 signaling during breast and neural development: novel genetic models reveal unique ErbB4 activities. Cell cycle (Georgetown, Tex.) 26 14504474
2003 Analysis of HER2 and HER4 in human myocardium to clarify the cardiotoxicity of trastuzumab (Herceptin). Breast cancer research and treatment 26 14672400
2023 Neuregulin4 Acts on Hypothalamic ErBb4 to Excite Oxytocin Neurons and Preserve Metabolic Homeostasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 25 37060105
2013 Investigational therapies targeting the ErbB (EGFR, HER2, HER3, HER4) family in GI cancers. Expert opinion on investigational drugs 25 23316969
2011 TNF-α converting enzyme-mediated ErbB4 transactivation by TNF promotes colonic epithelial cell survival. American journal of physiology. Gastrointestinal and liver physiology 25 21617117
1995 Localization of the human HER4/erbB-4 gene to chromosome 2. Oncogene 25 7700649
2020 Erbb4 regulates the oocyte microenvironment during folliculogenesis. Human molecular genetics 24 32716031
2014 ERBB4 mutation analysis: emerging molecular target for melanoma treatment. Methods in molecular biology (Clifton, N.J.) 24 24258993
2014 Convergent and divergent cellular responses by ErbB4 isoforms in mammary epithelial cells. Molecular cancer research : MCR 24 24829397
2011 Expression of the neuregulin receptor ErbB4 in the brain of the rhesus monkey (Macaca mulatta). PloS one 24 22087295
2010 ErbB4 promotes cyclooxygenase-2 expression and cell survival in colon epithelial cells. Laboratory investigation; a journal of technical methods and pathology 24 20585313
2010 Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. Molecular cancer research : MCR 24 20858735
2020 ErbB4 Mutation that Decreased NRG1-ErbB4 Signaling Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia. Journal of Alzheimer's disease : JAD 22 32065797
2018 HER4 promotes cell survival and chemoresistance in osteosarcoma via interaction with NDRG1. Biochimica et biophysica acta. Molecular basis of disease 22 29524631
2021 ErbB4 promotes inhibitory synapse formation by cell adhesion, independent of its kinase activity. Translational psychiatry 21 34226493
2019 ErbB4 promotes malignant peripheral nerve sheath tumor pathogenesis via Ras-independent mechanisms. Cell communication and signaling : CCS 21 31291965
2015 PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling. The international journal of biochemistry & cell biology 20 25681686
2018 The receptor tyrosine kinase ERBB4 is expressed in skin keratinocytes and influences epidermal proliferation. Biochimica et biophysica acta. General subjects 19 29410073
2010 Immunohistochemical expression of HER1, HER3, and HER4 in HER2-positive breast cancer patients treated with trastuzumab-containing neoadjuvant chemotherapy. Journal of surgical oncology 19 20087905
1999 Expression of c-erbB-4/HER4 is regulated in T47D breast carcinoma cells by retinoids and vitamin D3. Biochemical and biophysical research communications 19 10383375
1998 ErbB-4 ribozymes abolish neuregulin-induced mitogenesis. Cancer research 19 9699674
2021 Discovery of first-in-class imidazothiazole-based potent and selective ErbB4 (HER4) kinase inhibitors. European journal of medicinal chemistry 18 34237622
2020 Poziotinib suppresses ovarian cancer stem cell growth via inhibition of HER4-mediated STAT5 pathway. Biochemical and biophysical research communications 18 32201081
2014 Neuregulin 1-activated ERBB4 as a "dedicated" receptor for the Hippo-YAP pathway. Science signaling 18 25492964
2021 ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy. Circulation. Heart failure 17 34247489
2020 HER4 promotes the growth and metastasis of osteosarcoma via the PI3K/AKT pathway. Acta biochimica et biophysica Sinica 17 32181480
2012 ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response. Biochemical and biophysical research communications 17 22244893
2024 Structural dynamics of the active HER4 and HER2/HER4 complexes is finely tuned by different growth factors and glycosylation. eLife 16 38498590
2024 Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway. Acta pharmacologica Sinica 15 38589689
2019 Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS. Neuropathology : official journal of the Japanese Society of Neuropathology 15 31124187
2014 Desensitization by different strategies of epidermal growth factor receptor and ErbB4. Journal of pharmacological sciences 15 24553453
2002 ErbB-4: a receptor tyrosine kinase. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 15 11926320
2025 Small-molecule-induced ERBB4 activation to treat heart failure. Nature communications 14 39794341
2007 ErbB4 expression and mutation in Japanese patients with lung cancer. Clinical lung cancer 14 17681096

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