Affinage

ERBB4

Receptor tyrosine-protein kinase erbB-4 · UniProt Q15303

Length
1308 aa
Mass
146.8 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERBB4 (HER4) is a receptor tyrosine kinase of the EGF receptor family that transduces signals from neuregulins, HB-EGF, and betacellulin to regulate cell fate decisions spanning proliferation, differentiation, survival, and apoptosis in epithelial, glial, and neuronal lineages. Ligand binding activates ERBB4 kinase activity and triggers heterodimerization with HER1 or HER2, coupling to PI3K/Akt (via CYT-1 isoform-specific tyrosine 1056), Shc/MAPK, and SREBP-2 cholesterol biosynthesis pathways (PMID:8617750, PMID:11343971, PMID:26535009); the JM-a splice isoform undergoes TACE/ADAM17-mediated ectodomain shedding followed by presenilin/γ-secretase cleavage to release a soluble intracellular domain (4ICD) that translocates to the nucleus—where it coactivates STAT5A, estrogen receptor-α, HIF-1α, and AP-2—or to mitochondria, where it functions as a BH3-only-like proapoptotic factor requiring BAK for cytochrome c release (PMID:10744726, PMID:15746097, PMID:16778220, PMID:16912174, PMID:22308027, PMID:20943952). In the brain, ERBB4 is selectively expressed in GABAergic interneurons where it maintains excitatory synaptic inputs through PKC-dependent AMPA receptor trafficking, modulates interneuron intrinsic excitability by reducing voltage-gated sodium channel current density, regulates GABAA receptor surface levels via clathrin-mediated endocytosis, and promotes inhibitory synapse formation onto pyramidal neurons through a kinase-independent trans-synaptic interaction of its extracellular RLD domain with Slitrk3 (PMID:19793984, PMID:27641496, PMID:23035098, PMID:24218551, PMID:34226493). Loss-of-function mutations in the ERBB4 kinase and C-terminal domains (R927Q, R1275W) that reduce NRG1-induced autophosphorylation cause amyotrophic lateral sclerosis type 19 (PMID:24119685).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1993 High

    Identification of ERBB4 as the direct high-affinity receptor for heregulin/neuregulin resolved which ErbB family member mediates heregulin signaling, showing HER2 phosphorylation requires HER4 coexpression rather than direct ligand binding.

    Evidence Radioligand binding and tyrosine phosphorylation assays on cell lines expressing individual recombinant receptors

    PMID:7689552 PMID:7902537

    Open questions at the time
    • Structural basis of ligand–receptor specificity not determined
    • In vivo relevance of heregulin–HER4 binding not yet tested
  2. 1995 High

    Mapping ERBB4 autophosphorylation sites and downstream effectors (PI3K at Y1056, Shc at Y1188/Y1242) and demonstrating HER1–HER4 heterodimer transphosphorylation established the proximal signaling logic of the receptor, including the basis for heterodimerization-dependent signal amplification.

    Evidence In vitro kinase assays, peptide competition, co-immunoprecipitation in transfected NIH 3T3 cells; NMJ localization by immunohistochemistry

    PMID:7759543 PMID:8617750 PMID:8846777

    Open questions at the time
    • Isoform-specific coupling to PI3K not yet appreciated
    • No in vivo loss-of-function data
  3. 1996 High

    Demonstrating that HER4-driven transformation requires coexpression of HER1 or HER2 established that functional heterodimerization, not HER4 homodimerization alone, is the biologically relevant signaling unit for oncogenic output.

    Evidence NIH 3T3 focus formation assay with receptor combinations, correlated with transphosphorylation levels

    PMID:8632008

    Open questions at the time
    • Structural basis of heterodimer selectivity unknown
    • Does not address non-oncogenic functions
  4. 1997 High

    Discovery of JM-a and JM-b juxtamembrane splice isoforms, where only JM-a undergoes regulated ectodomain shedding, revealed that alternative splicing creates functionally distinct receptor pools with different proteolytic fates — a principle later central to nuclear signaling by ERBB4.

    Evidence RT-PCR of human/mouse tissues, phorbol ester stimulation, radioligand binding and Western blot for ectodomain loss; HB-EGF binding/chemotaxis assays; Co-IP of HER2–HER4 in oligodendrocytes

    PMID:9105049 PMID:9135143 PMID:9334263

    Open questions at the time
    • Identity of the sheddase protease not yet known
    • Fate of the membrane-tethered stub not characterized
  5. 2000 High

    Identification of TACE/ADAM17 as the metalloprotease required for JM-a ectodomain shedding, using TACE-null cells with genetic rescue, provided the first molecular identity for the regulated cleavage step and set up the two-step proteolytic release model for the intracellular domain.

    Evidence TACE knockout and reexpression in cell lines, constitutive and stimulated shedding assays

    PMID:10744726

    Open questions at the time
    • γ-secretase involvement not yet demonstrated
    • Signals controlling TACE access to HER4 unclear
  6. 2000 Medium

    Functional comparison of CYT-1 and CYT-2 cytoplasmic isoforms showed that only CYT-1 couples to PI3K/Akt (via its 16-amino-acid insert containing the PI3K docking site), while both activate Shc/MAPK, establishing isoform-specific downstream pathway engagement.

    Evidence Isoform-specific expression, PI3K activity assays, chemotaxis and survival readouts

    PMID:11343971

    Open questions at the time
    • Relative expression of CYT-1 vs CYT-2 in specific tissues not systematically mapped
    • In vivo consequences of isoform switching not addressed
  7. 2005 High

    Demonstration that presenilin/γ-secretase cleavage is required to release 4ICD for both nuclear (STAT5A coactivation) and mitochondrial (proapoptotic) functions completed the two-step proteolysis model and linked the receptor to regulated intramembrane proteolysis signaling.

    Evidence V673I transmembrane mutant blocking γ-secretase cleavage, nuclear/mitochondrial fractionation, STAT5A reporter, apoptosis assays

    PMID:15746097

    Open questions at the time
    • How 4ICD partitions between nucleus and mitochondria unknown
    • Endogenous stoichiometry of nuclear vs mitochondrial 4ICD not measured
  8. 2006 High

    Characterization of 4ICD as a BH3-only-like proapoptotic protein that interacts with BCL-2, requires BAK for cytochrome c release, and depends on an intact BH3 domain established the molecular mechanism of ERBB4-mediated apoptosis at mitochondria; simultaneously, nuclear 4ICD was shown to coactivate ERα at select promoters and to mediate heregulin-dependent growth inhibition through a JNK–BRCA1 axis.

    Evidence BH3 mutagenesis, BCL-2 Co-IP, BAK/BAX KO cells, cytochrome c release; Co-IP of 4ICD–ERα, ChIP, promoter-reporter; BRCA1-null isogenic cells with JNK inhibitor

    PMID:11390655 PMID:16778220 PMID:16912174 PMID:16914727

    Open questions at the time
    • Direct structural characterization of BH3 domain interaction with BCL-2 family members lacking
    • Relative contribution of nuclear vs mitochondrial 4ICD to breast cancer phenotype unresolved
  9. 2007 High

    CYT-2 ICD was shown to translocate to the nucleus more efficiently than CYT-1 ICD in a kinase-activity-dependent manner, and ErbB4 was found to regulate excitatory synapse strength and dendritic spine size in hippocampal neurons, establishing ERBB4 as a synaptic signaling receptor.

    Evidence K751R kinase-dead mutant, nuclear fractionation, in vitro kinase assay, STAT5 reporter; electrophysiology with overexpression and dominant-negative ErbB4 in hippocampal neurons

    PMID:17486069 PMID:17521571

    Open questions at the time
    • How kinase activity promotes nuclear import mechanistically unknown
    • Cell-type identity of ErbB4-expressing hippocampal neurons not resolved in these studies
  10. 2009 High

    Rigorous localization using ErbB4-null controls demonstrated that ErbB4 is selectively expressed in GABAergic interneurons (not pyramidal neurons) in the hippocampus, with accumulation at glutamatergic postsynaptic sites, reframing prior synaptic studies as interneuron-specific phenomena.

    Evidence Immunohistochemistry/immunoelectron microscopy validated against ErbB4-null mice, single-cell RT-PCR of identified neurons

    PMID:19793984

    Open questions at the time
    • Whether all interneuron subtypes express ErbB4 not resolved
    • Mechanism of synaptic targeting unknown
  11. 2010 High

    Discovery that JM-a-derived 4ICD associates with transcription factor AP-2 to drive PDGFRA transcription linked isoform-specific proteolytic processing to a survival pathway distinct from the canonical mitochondrial apoptotic function of 4ICD.

    Evidence Co-IP of 4ICD and AP-2, siRNA knockdown of AP-2 and PDGFRα, PDGF-BB rescue of JM-b cells

    PMID:20943952

    Open questions at the time
    • Whether AP-2–4ICD interaction occurs in vivo not tested
    • Genome-wide targets of 4ICD–AP-2 unknown
  12. 2012 High

    Nuclear 4ICD was shown to stabilize HIF-1α protein in a VHL-independent, RACK1-dependent manner, expanding the repertoire of 4ICD transcriptional coactivation to hypoxia signaling; separately, NRG1 was found to reduce interneuron intrinsic excitability by suppressing voltage-gated sodium channel currents, defining a non-synaptic mechanism of ErbB4 neuromodulation; and a crystal structure of the ErbB4 ectodomain mapped the cleavage-relevant subdomain IV region.

    Evidence Co-IP of 4ICD–HIF-1α, mammary-specific Erbb4 KO, HIF stability assay; electrophysiology with pan-ErbB inhibitor in dissociated interneurons; X-ray crystallography at 3.4 Å with antibody blockade in xenografts

    PMID:22308027 PMID:22761786 PMID:23035098

    Open questions at the time
    • Structural mechanism of HIF-1α stabilization by 4ICD not determined
    • Identity of sodium channel subtype modulated by ErbB4 not specified
  13. 2013 High

    Unbiased proteomics identified GABAA receptor α1 as an ErbB4 interactor, and NRG1/ErbB4 signaling was shown to reduce GABAAR surface levels on interneurons via PKC-dependent clathrin endocytosis, revealing ErbB4 as a regulator of inhibitory tone on interneurons themselves; concurrently, loss-of-function ERBB4 mutations causing ALS type 19 established a Mendelian disease link.

    Evidence Mass spectrometry, Co-IP, electrophysiology with clathrin/PKC inhibitors in ErbB4-null mice; whole-genome sequencing with autophosphorylation assays of R927Q and R1275W mutants

    PMID:24119685 PMID:24218551

    Open questions at the time
    • Structural basis of ErbB4–GABAAR interaction unknown
    • ALS19 mutations not yet validated in animal models of motor neuron disease
  14. 2015 High

    NRG1-activated ERBB4 was found to stimulate SREBP-2-dependent cholesterol biosynthesis through PI3K/mTORC1/2 (independent of AKT), revealing a metabolic output of the receptor not previously appreciated; activating ERBB4 mutations in lung cancer were shown to preferentially enhance ICD release rather than canonical Erk/Akt signaling.

    Evidence SREBP-2 cleavage assay, HMGCR/LDLR mRNA, pharmacological inhibitor panel; structural analysis and phosphorylation/ICD release assays for lung cancer mutants; PTPN21 dephosphorylation/Elk-1 assays

    PMID:25681686 PMID:26050618 PMID:26535009

    Open questions at the time
    • Physiological relevance of ErbB4-driven cholesterol synthesis in vivo not tested
    • Whether oncogenic mutant ICD reaches the nucleus and activates same targets as ligand-induced ICD unknown
  15. 2016 High

    In vivo monocular deprivation experiments demonstrated that NRG1/ErbB4 signaling maintains excitatory inputs onto PV interneurons through PKC-dependent AMPA receptor exocytosis, establishing ErbB4 as a mediator of experience-dependent synaptic plasticity in cortical circuits.

    Evidence Monocular deprivation, NRG1 injection rescue, PKC pharmacological inhibition, in vivo electrophysiology in visual cortex

    PMID:27641496

    Open questions at the time
    • Whether ErbB4 kinase activity or ICD release is the relevant signal for AMPAR exocytosis not dissected
    • Downstream PKC isoform identity unknown
  16. 2017 High

    NRG4-activated ErbB4 in pro-inflammatory macrophages was shown to trigger mitochondrial apoptosis dependent on proteolytic ICD generation, extending the BH3-only proapoptotic function beyond epithelial cells to immune regulation in vivo (colitis model).

    Evidence Macrophage ErbB4 expression profiling, NRG4 treatment, mitochondrial fractionation, membrane potential assay, protease inhibitors, DSS colitis model

    PMID:28230865

    Open questions at the time
    • Whether BAK dependence applies in macrophages as in epithelial cells not tested
    • ErbB4 isoform(s) expressed in macrophages not characterized
  17. 2018 High

    Acute chemical-genetic inactivation of ErbB4 kinase in interneurons disrupted hippocampal–prefrontal gamma synchrony and top-down attention, establishing a causal link between ErbB4 kinase activity in interneurons and cognitive circuit function.

    Evidence Analog-sensitive ErbB4 chemical genetics, optogenetic inhibition of ErbB4+ interneurons, LFP recordings, behavioral attention assay

    PMID:29628188

    Open questions at the time
    • Which downstream signaling pathway (AMPAR, Nav, GABAAR modulation) mediates the gamma synchrony effect is unresolved
    • Whether ICD-mediated transcription contributes to circuit-level phenotypes unknown
  18. 2021 High

    ErbB4 was found to promote inhibitory synapse formation through a kinase-independent trans-synaptic adhesion mechanism—its extracellular RLD domain interacts with Slitrk3—separating the receptor's adhesion and signaling functions in synaptogenesis for the first time.

    Evidence HEK293T–neuron co-culture synaptogenesis assay, K751M kinase-dead knock-in mice with normal inhibitory synapse numbers, RLD deletion, Slitrk3 neutralization, electrophysiology

    PMID:34226493

    Open questions at the time
    • Structural basis of RLD–Slitrk3 trans-interaction not determined
    • Whether kinase-independent adhesion function operates at excitatory synapses unknown
  19. 2023 High

    NRG4 signaling through ErbB4 in hypothalamic oxytocin neurons was shown to regulate energy balance, with oxytocin neuron-specific ErbB4 knockout accelerating diet-induced obesity, extending ERBB4 function to central metabolic control.

    Evidence Cell-type-specific ErbB4 knockout in oxytocin neurons, PVN-specific ErbB4 overexpression, central NRG4 infusion, oxytocin neuron ablation rescue

    PMID:37060105

    Open questions at the time
    • Downstream signaling cascade in oxytocin neurons (PI3K, MAPK, ICD release) not dissected
    • Whether ICD-mediated transcription in oxytocin neurons contributes to metabolic phenotype unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how 4ICD partitions between nuclear and mitochondrial fates, the structural basis of isoform-specific signaling and RLD–Slitrk3 trans-adhesion, whether kinase-dependent and kinase-independent functions of ErbB4 are coordinated in the same synapse, and the full spectrum of 4ICD transcriptional targets across cell types.
  • No systematic genome-wide identification of 4ICD transcriptional targets
  • No structural model of full-length ErbB4 in active homodimer or heterodimer state
  • Mechanism of 4ICD nuclear vs mitochondrial sorting uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0060089 molecular transducer activity 4 GO:0140110 transcription regulator activity 4 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005634 nucleus 4 GO:0005739 mitochondrion 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-112316 Neuronal System 5 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1430728 Metabolism 1
Partners
EGFRERBB2ERBB3ESR1GABRA1HIF1ASLITRK3STAT5A
Complex memberships
4ICD–ERα nuclear complex4ICD–STAT5A nuclear complexHER1–HER4 heterodimerHER2–HER4 heterodimer

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Heregulin (neuregulin) directly binds to and activates the intrinsic tyrosine kinase activity of HER4/p180erbB4, inducing tyrosine phosphorylation; heregulin fails to induce HER2 phosphorylation in the absence of HER4, indicating HER4 is required for heregulin signal transduction. Radioligand binding assays and tyrosine phosphorylation studies with recombinant ligand on cell lines expressing recombinant receptors Nature High 7902537
1993 A 45 kDa heparin-binding glycoprotein (p45, related to heregulin) specifically binds to and stimulates tyrosine phosphorylation of HER4/p180erbB4, inducing differentiation of MDA-MB-453 breast cancer cells; p45 does not bind HER2-expressing cells. Protein purification to homogeneity, N-terminal amino acid sequencing, binding and cross-linking experiments with recombinant receptors The Journal of biological chemistry High 7689552
1995 HER4 exhibits in vitro kinase activity and phosphorylates the p85 regulatory subunit of PI3-kinase and Shc adapter proteins; tyrosine 1056 was identified as the PI3-kinase binding site and tyrosines 1188 and 1242 as SHC binding sites; HER1 and HER4 form heterodimer complexes and transphosphorylate each other. In vitro kinase assay, peptide competition studies, co-immunoprecipitation, NIH 3T3 cell transfection The Journal of biological chemistry High 8617750
1995 Heregulin (HRG)-beta2 EGF-like domain activates HER4 tyrosine phosphorylation and induces tyrosine phosphorylation of Shc adapter proteins, implicating Shc in HER4 downstream signaling. Recombinant HRG-Fc fusion proteins, HER4-expressing cell lines, tyrosine phosphorylation assays The Journal of biological chemistry High 7759543
1995 ErbB3 and ErbB4 are concentrated at neuromuscular synaptic sites in postsynaptic membrane of adult rodent skeletal muscle, consistent with NRG-stimulated synaptic signaling for AChR gene expression. Immunohistochemistry with anti-ErbB antibodies, denervation experiments The EMBO journal Medium 8846777
1996 HER4 transformation of NIH 3T3 cells requires coexpression of HER1 or HER2; NDF-induced transphosphorylation between receptors correlates with synergistic transformation, demonstrating functional heterodimerization is required for full oncogenic signaling. NIH 3T3 cell transfection with receptor combinations, focus formation assay, receptor phosphorylation experiments The Journal of biological chemistry High 8632008
1997 HB-EGF binds to and activates HER4 independently of HER1, inducing HER4 tyrosine phosphorylation and PI3-kinase association, leading to chemotaxis but not proliferation; this contrasts with HER1, where HB-EGF stimulates both proliferation and chemotaxis. Radioligand binding to NIH 3T3 overexpressing individual receptors, tyrosine phosphorylation assays, PI3-K activity assay with wortmannin inhibition, chemotaxis assay The EMBO journal High 9135143
1997 Two HER4 juxtamembrane isoforms (JM-a with 23 aa insert and JM-b with 13 aa insert) are differentially expressed in tissues; JM-a but not JM-b undergoes proteolytic shedding in response to phorbol ester, indicating the JM region determines susceptibility to cleavage. RT-PCR of human/mouse tissues, in situ hybridization, phorbol ester treatment, 125I-NRG binding assay, Western blot for receptor loss The Journal of biological chemistry High 9334263
1997 Neuregulin signals to oligodendrocyte lineage cells via HER4 phosphorylation (with HER2 as a physical partner but not phosphorylated), while Schwann cells use HER2:HER3 heterodimers; HER2 co-immunoprecipitates with HER4 in oligodendrocytes. Tyrosine phosphorylation assays in O2A cells and oligodendrocytes, co-immunoprecipitation The Journal of cell biology High 9105049
2000 TACE (tumor necrosis factor-alpha-converting enzyme/ADAM17) is the metalloprotease essential for regulated ectodomain shedding of HER4 JM-a isoform; TACE-null cells lack HER4 JM-a cleavage, and re-expression of TACE restores constitutive and phorbol ester-stimulated processing. TACE knockout cell lines, reexpression of TACE, phorbol ester and pervanadate stimulation, Western blot for cleavage products The Journal of biological chemistry High 10744726
2000 ErbB4 CYT-1 and CYT-2 cytoplasmic isoforms both couple to the Shc-MAPK pathway and stimulate proliferation, but only CYT-1 can activate PI3-K/Akt signaling, which is required for survival and chemotaxis responses. Cell-based signaling assays, isoform-specific expression, PI3-K activity assays, chemotaxis assay, survival assay Trends in cardiovascular medicine Medium 11343971
2001 HER4 is both necessary and sufficient for heregulin-dependent antiproliferative and differentiation responses in breast cancer cells; kinase-inactive HER4 abrogates the response, and HB-EGF (acting through HER4 in EGFR-negative cells) reproduces growth inhibition. Stable expression of kinase-inactive HER4 dominant negative, introduction of HER4 into HER4-negative cells, single-chain anti-HER2 antibody to sequester HER2, proliferation and differentiation assays Molecular and cellular biology High 11390655
2005 Presenilin-dependent gamma-secretase cleaves HER4 to release the intracellular domain (4ICD); an ERBB4-V673I transmembrane mutant that blocks gamma-secretase processing prevents nuclear accumulation of 4ICD, abolishes STAT5A-driven beta-casein promoter activation, and eliminates mitochondrial 4ICD accumulation and proapoptotic activity. Site-directed mutagenesis (V673I), gamma-secretase inhibitor, nuclear fractionation, STAT5A reporter assay, mitochondrial fractionation, apoptosis assay The Journal of biological chemistry High 15746097
2006 The ERBB4 intracellular domain (4ICD) functions as a BH3-only protein: after ligand-induced proteolytic processing, 4ICD accumulates at mitochondria causing cytochrome c efflux; 4ICD requires an intact BH3 domain, interacts with BCL-2, and requires BAK (not BAX) for apoptotic signaling. Ligand-induced processing assay, mitochondrial fractionation, BH3 domain mutagenesis, BCL-2 co-immunoprecipitation, BAK/BAX knockout cell lines, cytochrome c release assay Cancer research High 16778220
2006 The proteolytically processed ERBB4 intracellular domain (4ICD) translocates to the nucleus in an estrogen/ER-dependent manner, physically associates with estrogen receptor alpha (ERα), and selectively coactivates ER transcription at PgR and SDF-1 but not pS2 promoters; ERBB4 itself is estrogen-inducible via an ERE half-site. Co-immunoprecipitation of ERα and 4ICD, siRNA knockdown, ChIP assay, promoter-reporter assay, nuclear fractionation, cell proliferation assay Cancer research High 16912174
2006 HER4-mediated growth inhibition of breast cancer cells requires BRCA1; heregulin/HER4 activates JNK to upregulate BRCA1, and BRCA1 knockdown or genetic deletion abolishes HER4-dependent G2/M delay. siRNA knockdown of BRCA1, pharmacological JNK inhibition, isogenic BRCA1-null mouse mammary epithelial cells, cell cycle analysis, Western blot for BRCA1 induction Molecular and cellular biology High 16914727
2007 ErbB4 CYT-2 ICD translocates to the nucleus more efficiently than CYT-1 ICD; nuclear translocation of ICD2 depends on its kinase activity (K751R mutation blocks translocation), not on differential ubiquitylation or stability; ICD2 shows greater in vitro kinase activity and is more efficient at STAT5 target gene (beta-casein) activation. Confocal microscopy, nuclear fractionation, in vitro kinase assay, site-directed mutagenesis (K751R), STAT5 reporter assay, metabolic stability and ubiquitylation assays 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; blocking NRG1/ErbB4 signaling destabilizes synaptic AMPA receptors and causes loss of NMDA currents and spines. Electrophysiology (whole-cell patch clamp), ErbB4 overexpression in hippocampal neurons, dominant-negative ErbB4, imaging of dendritic spines Neuron High 17521571
2009 ErbB4 is selectively expressed in GABAergic interneurons (not pyramidal neurons) of the rodent hippocampus; ultrastructural analysis shows ErbB4 accumulates at and adjacent to glutamatergic postsynaptic sites on interneurons, with somatodendritic but not presynaptic localization. Immunohistochemistry with validated monoclonal antibodies using ErbB4-null mice as negative controls, single-cell RT-PCR of electrophysiologically identified pyramidal neurons, immunoelectron microscopy The Journal of neuroscience High 19793984
2010 ErbB4 JM-a isoform promotes cell survival while JM-b promotes starvation-induced death; soluble 4ICD from JM-a associates with transcription factor AP-2, enhancing PDGFRA transcription, and survival of JM-a cells requires PDGFR-α and AP-2. Isoform-specific expression in fibroblasts, co-immunoprecipitation of 4ICD with AP-2, siRNA targeting PDGFR-α and AP-2, PDGF-BB rescue of JM-b cells, cell survival assays Molecular biology of the cell High 20943952
2011 Alternative splicing of ERBB4 produces structurally and functionally distinct CYT-1 and CYT-2 cytoplasmic isoforms and JM-a/JM-b juxtamembrane isoforms, with isoform-specific differences in PI3K coupling, nuclear localization, apoptosis, and proteolytic processing. Review with novel isoform expression and signaling data, functional assays Cell cycle Medium 21811097
2012 Cleaved ErbB4 intracellular domain directly interacts with HIF-1α in the nucleus and stabilizes HIF-1α protein against proteasomal degradation in a VHL/proline hydroxylation-independent but RACK1-dependent mechanism, promoting HIF-1α target gene transcription. Co-immunoprecipitation of 4ICD and HIF-1α, proteasome inhibitor assay, gamma-secretase inhibitor, mammary epithelial-specific Erbb4 knockout, HIF-1α stability assay, HRE-reporter assay The Journal of biological chemistry High 22308027
2012 ErbB4 ectodomain shedding is enhanced by estradiol in vitro; a 3.4 Å X-ray crystal structure of ErbB4 ectodomain complexed with anti-ErbB4 mAb 1479 localized the antibody binding site to subdomain IV at residues necessary for cleavage; mAb 1479 blocks ErbB4 cleavage in xenografts in vivo. X-ray crystallography (3.4 Å), ELISA for shed ectodomain, estradiol stimulation, xenograft tumor model with mAb treatment PloS one High 22761786
2013 ErbB4 interacts with GABAA receptor α1 subunit (GABAR α1) as identified by unbiased proteomics; NRG1/ErbB4 signaling, independent of receptor tyrosine kinase activity, reduces postsynaptic GABAR currents on hippocampal interneurons via clathrin-mediated endocytosis and PKC activation. Unbiased proteomics (mass spectrometry), co-immunoprecipitation, electrophysiology, pharmacological inhibitors of clathrin endocytosis and PKC, ErbB4-null mice Proceedings of the National Academy of Sciences of the United States of America High 24218551
2013 ERBB4 mutations within the tyrosine kinase domain (R927Q) or C-terminal domain (R1275W) reduce ErbB4 autophosphorylation upon NRG-1 stimulation, establishing that loss of NRG1-ErbB4 signaling contributes to ALS type 19 pathogenesis. Whole-genome sequencing, autophosphorylation assay of mutant vs. wild-type ErbB4 after NRG-1 stimulation American journal of human genetics Medium 24119685
2014 DOCK7, a DOCK180 family member, functions as a cytoplasmic activator of ErbB4 receptor tyrosine kinase in chandelier cells; DOCK7-ErbB4 pathway controls chandelier cell cartridge and bouton development in cortical circuits. In utero electroporation-based genetic labeling and manipulation of chandelier cells, DOCK7 knockdown, ErbB4 activity assay, morphological analysis Cell reports Medium 24440718
2015 Activating ERBB4 mutations in lung adenocarcinoma (Y285C, D595V, D931Y, K935I) enhance ErbB4 homodimerization and ErbB4-ErbB2 heterodimerization at extracellular or kinase domain interfaces, increase basal and ligand-induced phosphorylation, and selectively enhance proteolytic release of ErbB4 ICD over canonical Erk/Akt signaling. Structural analysis of mutant positions, ErbB4 phosphorylation assays, dimerization assay, NIH 3T3 serum-free survival assay, Western blot for ICD release Oncogene Medium 26050618
2015 NRG1-activated ERBB4 stimulates the SREBP-2 cholesterol biosynthetic pathway to increase LDL uptake and cholesterol biosynthesis gene expression; this pathway requires PI3K and mTORC1/2 but not AKT, and is blocked by pan-ErbB inhibitor lapatinib but not EGFR-selective erlotinib. ERBB4 ICD expression, NRG1 ligand stimulation, SREBP-2 cleavage assay, HMGCR/HMGCS1/LDLR mRNA quantification, pharmacological inhibitor panel, cholesterol uptake assay Science signaling High 26535009
2016 NRG1/ErbB4 signaling in PV interneurons maintains excitatory synaptic inputs to those cells; monocular deprivation downregulates NRG1/ErbB4 signaling in PV neurons causing retraction of excitatory inputs; exogenous NRG1 restores excitatory inputs through PKC-dependent AMPA receptor exocytosis. Monocular deprivation paradigm in mice, NRG1 injection, pharmacological PKC inhibition, electrophysiology, in vivo visual cortical response recording Neuron High 27641496
2017 ErbB4 localizes to mitochondria in pro-inflammatory macrophages; NRG4-activated ErbB4 induces mitochondrial apoptosis (loss of membrane potential) in activated macrophages, dependent on proteases generating the cleaved ErbB4 ICD; in vivo NRG4 administration reduces colonic macrophage numbers and ameliorates DSS colitis. ErbB4 expression in macrophage subtypes, NRG4 treatment, mitochondrial localization by fractionation, membrane potential assay, protease inhibitor experiments, DSS colitis mouse model with NRG4 administration Cell death & disease High 28230865
2018 ErbB4 in hippocampal interneurons is required for hippocampal-prefrontal gamma synchrony; acute chemical-genetic inactivation of ErbB4 kinase or optogenetic inhibition of ErbB4+ interneurons reduces GABA activity, impairs synchrony, and diminishes top-down attention. Chemical genetics (analog-sensitive ErbB4), optogenetics, local field potential recordings, behavioral top-down attention assay in mice Neuron High 29628188
2018 ErbB4 interacts with NDRG1 to promote osteosarcoma cell survival under stress; NDRG1 overexpression rescues HER4 knockdown-induced apoptosis in nutrient-deprived or cytotoxic conditions. Co-immunoprecipitation of HER4 and NDRG1, shRNA knockdown, cell survival assays, NDRG1 overexpression rescue Biochimica et biophysica acta. Molecular basis of disease Medium 29524631
2018 S100A4 protein signals through ErbB4 and its ligand NRG1 to promote neuronal survival; S100A4 also binds ErbB1 and ErbB3; neuroprotection by S100A4 requires ErbB4 expression and downstream ErbB2/Akt signaling. Biotinylated receptor tracking, immunoprecipitation, ErbB4 blockade (functional antibody/NRG neutralization), cell survival assays in dopaminergic neuron models Theranostics Medium 30083275
2021 ErbB4 promotes inhibitory synapse formation onto pyramidal neurons through kinase-independent cell adhesion: ErbB4 interacts in trans with Slitrk3 via its extracellular RLD domain; deletion of RLD or neutralization of Slitrk3 decreases inhibitory synapses and impairs GABAergic transmission; kinase-dead K751M knock-in mice have normal inhibitory synapse numbers. HEK293T/neuron co-culture synaptogenesis assay, K751M kinase-dead ErbB4 knock-in mice, RLD domain deletion construct, Slitrk3 neutralization, gephyrin/GABAAR α1 puncta quantification, electrophysiology Translational psychiatry High 34226493
2015 PTPN21 phosphatase de-phosphorylates ErbB4, paradoxically upregulating downstream ErbB4 signaling; kinase-dead ErbB4 (K751R) or phosphatase-dead PTPN21 (C1108S) impede PTPN21-dependent signaling; PTPN21 promotes NRG3 expression via Elk-1, linking ErbB4 signaling to NRG3 upregulation. Biotinylated receptor tracking, immunoprecipitation, kinase-dead and phosphatase-dead mutants, Elk-1 activation assay, NRG3 promoter analysis The international journal of biochemistry & cell biology Medium 25681686
2023 Neuregulin 4 (NRG4) acts on ErbB4 in oxytocin neurons of the hypothalamic paraventricular nucleus to excite these neurons and regulate energy balance; ErbB4 knockout specifically in oxytocin neurons accelerates diet-induced obesity; central NRG4 infusion reduces obesity via ErbB4 activation. ErbB4 phosphorylation in DIO mice, PVN-specific ErbB4 overexpression and Oxt neuron-specific ErbB4 knockout, central NRG4 infusion, oxytocin ablation rescue experiment Advanced science High 37060105
2012 NRG1 directly attenuates ErbB4-expressing interneuron intrinsic excitability by depolarizing firing threshold, primarily through ~60% reduction in voltage-gated sodium channel current density, independent of ErbB4-negative neurons. Pharmacological isolation of ErbB4+ interneurons, whole-cell patch clamp, pan-ErbB inhibitor PD158780, dissociated hippocampal cultures lacking dopaminergic innervation The Journal of neuroscience High 23035098

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature 471 7902537
1997 Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. The EMBO journal 309 9135143
2007 The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron 291 17521571
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