Affinage

NRG1

Pro-neuregulin-1, membrane-bound isoform · UniProt Q02297

Length
640 aa
Mass
70.4 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRG1 (neuregulin-1) is an EGF-family ligand that drives ErbB receptor tyrosine kinase signaling to control differentiation, proliferation, survival, and tissue morphogenesis across the nervous system, heart, and epithelia (PMID:8780647, PMID:29743679). It binds with high affinity to ErbB3 and ErbB4 and induces receptor hetero-oligomerization into high-molecular-weight complexes, with ErbB2 (Neu/HER2) acting as a co-receptor that decelerates ligand dissociation and prolongs downstream activation of MAP kinase (ERK), SAPK/JNK, p38, and PI3K-coupled signaling (PMID:8096177, PMID:8045292, PMID:8617201, PMID:9400997). NRG1 exists in multiple isoforms with distinct developmental and activity-dependent expression patterns, and type IV induction is CREB-dependent through a CRE element in its 5' UTR (PMID:21653853). Through ErbB receptors, NRG1 functions as a mitogen and survival/differentiation regulator for oligodendrocyte progenitors and Schwann cells (the latter via an autocrine loop), governs radial glial maintenance and neuronal migration partly via brain lipid-binding protein, and shapes Pacinian corpuscle formation and enteric nervous system development through specific isoforms (PMID:8780647, PMID:9417836, PMID:9342043, PMID:27707970, PMID:33497358). Peripheral myelination requires the PDZ protein Erbin, which stabilizes ErbB2 and sustains NRG1 signaling (PMID:19458253). In the heart, endocardial/myocardial NRG1-ErbB2-ERK signaling controls cardiomyocyte oriented division, trabeculation, ECM synthesis, and Yap1 localization, acting antagonistically with NOTCH1 (PMID:29743679, PMID:37846569). NRG1 also signals to GABAergic ErbB4-expressing interneurons to modulate inhibitory transmission and anxiety, a pathway antagonized by DISC1 and pharmacologically by spironolactone (PMID:25308353, PMID:26656849, PMID:28743784), and its abundance in the prefrontal cortex is controlled by Nedd4l-mediated ubiquitination in stress responses (PMID:32703967). NRG1 drives oncogenesis: chromosomal fusions (CD74-NRG1, VAMP2-NRG1, and others) present the EGF-like domain to activate ERBB2-ERBB3 (and HER4/EGFR) heterodimers and the PI3K-AKT axis, promoting transformation, while paracrine NRG1 from cancer-associated fibroblasts sustains ERBB3-AKT signaling and confers therapy resistance (PMID:24469108, PMID:26134228, PMID:26837769, PMID:25952648, PMID:37775182). NRG1 fusions signal primarily through HER3-HER2 heterodimerization, and the bispecific HER2×HER3 antibody zenocutuzumab blocks NRG1-HER3 binding and produces clinical responses across NRG1 fusion-positive tumors (PMID:35135829, PMID:39908431).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Established that NRG1 (NDF) is a high-affinity ligand engaging Neu/HER2 plus an additional co-component and couples receptor activation to PI3-kinase, defining its receptor system.

    Evidence Radiolabeled NDF crosslinking, antibody blocking, and PI3K co-IP in mammary cells

    PMID:8096177

    Open questions at the time
    • Identity of the additional co-receptor not resolved
    • Cell-type specificity of PI3K coupling unexplained
  2. 1994 High

    Identified ErbB3 as a direct NRG1 receptor whose engagement induces hetero-oligomerization, answering which receptor transduces the ligand signal.

    Evidence 125I-NDF crosslinking, anti-ErbB3 immunoprecipitation, and tyrosine phosphorylation assays

    PMID:8045292

    Open questions at the time
    • Composition of the >400 kDa complex not defined
    • Relative contributions of ErbB2 vs ErbB4 not yet dissected
  3. 1996 High

    Defined ErbB2's co-receptor mechanism, showing it decelerates ligand dissociation to prolong ERK/SAPK signaling, explaining how heterodimer composition tunes signal duration.

    Evidence Reciprocal co-IP, ER-trap intracellular antibody, ligand dissociation kinetics, and downstream kinase assays

    PMID:8617201

    Open questions at the time
    • Structural basis of decelerated dissociation not shown
    • Quantitative link between signal duration and cell fate not established
  4. 1996 High

    Established NRG1 as a mitogen, survival, and differentiation-modulating factor for glial and neuronal lineages, defining its role in nervous system development.

    Evidence Oligodendrocyte/retinal cell proliferation, survival, and neurite assays with ErbB activation and antibody blocking

    PMID:8625831 PMID:8780647

    Open questions at the time
    • Isoform responsible not resolved
    • In vivo relevance of differentiation inhibition incomplete
  5. 1997 High

    Connected NRG1 to cortical development and Schwann cell biology, showing it drives radial glial maintenance/neuronal migration and an autocrine Schwann cell proliferative loop.

    Evidence In vitro migration assays, ErbB2-deficient mice, BLBP analysis, ELISA secretion detection, and antibody neutralization

    PMID:9342043 PMID:9417836 PMID:9419971

    Open questions at the time
    • Mechanism of BLBP induction downstream of NRG1 not detailed
    • Isoform-specific autocrine signaling not yet dissected
  6. 2011 Medium

    Defined NRG1 isoform diversity and activity-dependent transcriptional control, showing type IV induction is CREB-mediated, explaining how neuronal activity regulates ligand availability.

    Evidence Isoform-specific qPCR, in situ hybridization, and CRE reporter/CREB binding analysis

    PMID:21653853

    Open questions at the time
    • Functional consequences of activity-induced isoforms in vivo not established
    • Regulation of other isoforms incompletely defined
  7. 2009 High

    Identified Erbin as an essential cofactor that stabilizes ErbB2 to enable NRG1-dependent peripheral myelination, revealing a structural requirement for signaling.

    Evidence Erbin-null and PDZ-deletion knockin mice, ErbB2 stability assays, Erbin-ErbB2 co-IP, and nerve conduction measurements

    PMID:19458253

    Open questions at the time
    • How Erbin biochemically stabilizes ErbB2 not fully resolved
    • Generalization beyond peripheral nerve untested
  8. 2014 High

    Placed NRG1-ErbB4 signaling in GABAergic interneuron circuits and linked it to TrkB/BDNF and NMDA receptor regulation, defining its neuromodulatory role.

    Evidence Co-IP/PLA of TrkB-ErbB4, TrkB knockout/siRNA, pharmacology, BDNF neutralization, BLA electrophysiology and behavior

    PMID:25052836 PMID:25308353

    Open questions at the time
    • Direct ErbB4-TrkB binding interface not mapped
    • Behavioral circuit specificity incompletely defined
  9. 2015 High

    Showed DISC1 antagonizes NRG1-ErbB4 signaling via competition for PSD95 binding, providing a mechanistic node linking the pathway to interneuron circuit phenotypes.

    Evidence Cell-type-specific DISC1 modulation, mutant DISC1 knockin mice, ErbB4/PSD95 binding competition, electrophysiology

    PMID:26656849

    Open questions at the time
    • Stoichiometry of DISC1-ErbB4-PSD95 competition unresolved
    • Disease relevance not directly tested
  10. 2014 High

    Demonstrated that NRG1 gene fusions (CD74-NRG1) present the EGF-like domain extracellularly to activate ERBB2-ERBB3 and PI3K-AKT, establishing NRG1 as an oncogenic driver.

    Evidence Transcriptome sequencing, ectopic fusion expression, phospho-receptor assays, and soft agar colony formation

    PMID:24469108

    Open questions at the time
    • Range of partner genes not fully cataloged
    • Therapeutic targeting not yet defined at this stage
  11. 2015 High

    Extended NRG1 fusion biology to additional partners and downstream circuits, including VAMP2-NRG1 membrane display and CD74-NRG1-driven NF-κB/IGF2 autocrine stemness.

    Evidence Ectopic fusion expression, phospho-signaling, sphere/colony formation, xenografts, and pharmacologic pathway dissection

    PMID:26134228 PMID:26837769

    Open questions at the time
    • Generality of IGF2 circuit across fusion types untested
    • Relative oncogenic potency of different fusions not compared
  12. 2021 High

    Established paracrine NRG1 from cancer-associated fibroblasts as a driver of ERBB3-AKT signaling and KRAS-bypass/therapy resistance, defining a stromal source of pathway activation.

    Evidence Conditioned medium, genetic/pharmacologic ERBB2/3 and NRG1 inhibition in human and murine PDAC and uveal melanoma models

    PMID:25952648 PMID:29935372 PMID:37775182

    Open questions at the time
    • Triggers of CAF NRG1 secretion not defined
    • Clinical translatability of stromal targeting incompletely tested
  13. 2018 High

    Defined NRG1-ErbB roles in organ morphogenesis and metabolism, including cardiac trabeculation/ECM synthesis, salivary acinar specification via mTORC2, and central metabolic control via POMC neurons.

    Evidence Cardiac-specific mutant mice, Erbb3 conditional KO with NRG1 epithelial treatment, scRNA-seq, and engineered NRG1-Fc with POMC electrophysiology

    PMID:29515030 PMID:29743679 PMID:36413949 PMID:37846569

    Open questions at the time
    • Isoform/receptor selectivity across these tissues not unified
    • Direct receptor identity for hypothalamic effect not fully resolved
  14. 2021 High

    Provided human genetic and developmental evidence that NRG1/ERBB3/ERBB2 signaling is essential for enteric nervous system and peripheral neural development, linking the pathway to a Mendelian developmental syndrome.

    Evidence Trio-exome sequencing, patient fibroblast RT-qPCR/immunoblot, mouse scRNA-seq, and conditional ErbB3 knockout

    PMID:33497358

    Open questions at the time
    • Pathogenic NRG1 variants (vs ERBB3/2) not directly demonstrated here
    • Genotype-phenotype range incompletely defined
  15. 2020 High

    Identified Nedd4l as the E3 ligase controlling NRG1 protein abundance post-translationally in the prefrontal cortex, linking ligand turnover to stress susceptibility.

    Evidence Ubiquitination assay and bidirectional viral Nedd4l manipulation in a chronic social defeat stress model

    PMID:32703967

    Open questions at the time
    • Ubiquitination site on NRG1 not mapped
    • Whether this regulates secreted vs membrane NRG1 unclear
  16. 2025 High

    Validated HER3-HER2 heterodimerization as the primary oncogenic mechanism of NRG1 fusions by demonstrating clinical efficacy of zenocutuzumab, which blocks NRG1-HER3 binding.

    Evidence Bispecific antibody mechanistic assays in isogenic/PDX models plus a Phase 2 registrational trial across 12 tumor types

    PMID:35135829 PMID:37678511 PMID:39908431

    Open questions at the time
    • Resistance mechanisms (HER4/EGFR contributions) require fuller dissection
    • Predictors of the ~30% response rate not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct NRG1 isoforms, membrane vs secreted forms, and receptor heterodimer combinations are matched to specific cellular outcomes across tissues remains incompletely defined.
  • No unified structural model linking isoform to receptor heterodimer selectivity
  • Quantitative rules relating signal duration to fate decisions absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3
Partners
ERBB1ERBB2ERBB3ERBB4ERBINNEDD4L

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 NDF (NRG1) binds with high affinity (Kd ~10^-9 M) to mammary cells via Neu/HER-2 and an additional cellular co-component; direct radiolabeled cross-linking showed covalent association with Neu in breast but not ovarian cells, and NDF-induced Neu activation was coupled to PI3-kinase association in a cell-type-specific manner. Radiolabeled NDF cross-linking, monoclonal antibody blocking, direct binding analysis, PI3K co-immunoprecipitation The EMBO journal High 8096177
1994 NDF (NRG1) stimulates tyrosine phosphorylation of Her3/ErbB3, and chemical crosslinking of radiolabeled NDF to cells immunoprecipitated with anti-Her3 reveals a high-molecular-weight complex (>400 kDa), indicating NDF is a ligand for ErbB3 that induces receptor hetero-oligomerization. Tyrosine phosphorylation assay, 125I-NDF crosslinking, immunoprecipitation FEBS letters High 8045292
1995 NDF (NRG1) activates MAP kinase (p44ERK1/p42ERK2) and p70/p85 S6 kinase, and stimulates tyrosine phosphorylation and in vitro kinase activity of ErbB-2 in mammary epithelial cells; PKC activation by TPA blocks NDF-induced ErbB-2 activation and cell proliferation. In vitro kinase assay, MAP kinase activation assay, TPA-mediated PKC activation Oncogene High 7824269
1996 ErbB-2 forms heterodimers with EGF receptor (ErbB-1) and NDF receptors (ErbB-3 and ErbB-4); ErbB-2 overexpression enhances binding affinity to NDF by decelerating ligand dissociation, while ER-trapped anti-ErbB-2 antibody removes ErbB-2 from cell surface and almost completely abolishes NDF binding by accelerating dissociation. These kinetic effects prolong MAP kinase (ERK) and c-Jun kinase (SAPK) activation. Co-immunoprecipitation of heterodimers, intracellular antibody (ER-trap) blocking, ligand dissociation kinetics, ERK/SAPK activation assays The EMBO journal High 8617201
1996 GGF/neuregulin (NRG1) acts as a mitogen and survival factor for oligodendrocyte progenitors (O4+/O1- cells) and oligodendrocytes; high GGF levels reversibly inhibit differentiation and lineage commitment. GGF activates all three ErbB receptors expressed by progenitors (ErbB2, ErbB3, ErbB4). Cortical neurons release a soluble GGF-like mitogen for pro-oligodendrocytes that is blocked by anti-GGF antibodies. Cell proliferation/survival assays, ErbB receptor activation assays, antibody blocking of conditioned medium Neuron High 8780647
1996 GGF/neuregulin (NRG1) promotes survival and neurite extension from embryonic and neonatal rat retinal neurons in a dose-dependent manner, with effects correlating with erbB2/neu expression levels during retinal development. Dissociated retinal cell cultures, neuronal survival and neurite outgrowth assays, receptor expression analysis Development (Cambridge, England) Medium 8625831
1997 GGF (NRG1) promotes neuronal migration along radial glial fibers and maintenance/elongation of radial glial cells during cortical development; loss of GGF signaling via ErbB2 receptors causes abnormal radial glial development. GGF's regulation of radial glia is mediated in part through brain lipid-binding protein (BLBP). In vitro neuronal migration assays, ErbB2-deficient mouse models, BLBP expression analysis Development (Cambridge, England) High 9342043
1997 ErbB-3 (NDF/NRG1 receptor) is expressed primarily in epithelial layers, peripheral nervous system, and adult brain; ErbB-4 is restricted to developing CNS and embryonic heart. Blocking endogenous NDF with soluble ErbB-4 accelerated neurite outgrowth in primary brain cultures and P19 teratocarcinoma, demonstrating an inhibitory role of NDF on neural differentiation. ErbB-3 is associated with proliferation while ErbB-4 correlates with differentiated phenotype in P19 cells. Soluble receptor blocking, primary brain culture neurite outgrowth assay, P19 differentiation assay Oncogene Medium 9419971
1997 NDF/NRG1 activates ErbB3-ErbB2 crosstalk in LNCaP prostate cells without involving ErbB1; NDF activates PI3K (forming an 'activation complex' with ErbB3), ERK/MAPK, mHOG/p38, and JNK/SAPK pathways, but not PLCγ or STAT family signaling, demonstrating a distinct signaling pattern from TGF-α. Tyrosine phosphorylation assays, PI3K co-immunoprecipitation, pathway activation assays in prostate cell lines Oncogene Medium 9400997
1997 Schwann cells secrete a ~45 kDa neuregulin protein (NRG1) and show constitutive activation of ErbB3, indicating an autocrine loop. Anti-neuregulin antibody inhibited Schwann cell proliferation stimulated by neurons and by multiple unrelated mitogens (bFGF, HGF, TGF-β1), implicating NRG1 autocrine signaling in Schwann cell mitogenic responses. ELISA detection of secreted neuregulin, ErbB3 phosphorylation assays, antibody neutralization of proliferation assays Experimental neurology Medium 9417836
1999 GGF/NRG1 induces phenotypic reversion of differentiated oligodendrocytes: loss of MBP expression, re-expression of nestin, reorganization of actin cytoskeleton, and reduction in process number. GGF is not cytotoxic but enhances survival. GGF rapidly activates PI3-kinase and MAP kinase signaling pathways in oligodendrocytes. TUNEL assay, immunostaining for MBP/nestin, PI3K and MAPK activation assays Molecular and cellular neurosciences Medium 10192767
2009 Erbin, a PDZ domain protein that interacts specifically with ErbB2, is required for NRG1 signaling and myelination of the peripheral nervous system. Erbin stabilizes ErbB2 protein; loss of the Erbin PDZ domain causes ErbB2 instability and compromised NRG1 signaling. Erbin null mice and erbin(DeltaC/DeltaC) mice show hypomyelination, aberrant Remak bundle formation, reduced nerve conduction velocity, and sensory threshold changes. Genetic knockout/knock-in mouse models, ErbB2 protein stability assays, nerve conduction velocity measurement, co-immunoprecipitation of Erbin-ErbB2 Proceedings of the National Academy of Sciences of the United States of America High 19458253
2009 NRG1/ERBB3 signaling inhibits melanocyte maturation and promotes undifferentiated, migratory, and proliferative characteristics; NRG1/ERBB3 signaling is necessary and sufficient to inhibit differentiation of late-stage melanocyte progenitors in culture. NRG1 treatment increases proliferation and invasion of melanocytes with decreased differentiation gene expression. ERBB3-deficient embryonic analysis, NRG1 treatment of melanocyte cultures, proliferation/invasion assays, gene expression analysis Pigment cell & melanoma research Medium 19659570
2010 LH induces NRG1 type III transcripts in granulosa cells via ERK1/2 and C/EBPβ-dependent mechanisms. NRG1 (intact 75 kDa and secreted 45 kDa forms) binds to ERBB3/ERBB2 complexes in granulosa cells and selectively stimulates AKT phosphorylation over ERK1/2. NRG1 potentiates AREG-induced ERK1/2 phosphorylation and progesterone production, and enhances oocyte developmental competence in cumulus-oocyte complexes. Western blotting, receptor phosphorylation assays, progesterone measurement, oocyte developmental competence assay Molecular endocrinology (Baltimore, Md.) Medium 21047912
2011 Each of the six NRG1 isoform types has a distinct expression pattern in the brain at different developmental ages. Types I, II, and III are predominantly expressed in excitatory neurons. Neuronal activity specifically regulates NRG1 isoform expression: type I and IV NRG1 levels increase with neuronal activity. Type IV regulation requires a CRE cis-element in the 5' UTR that binds to CREB. Isoform-specific qPCR, in situ hybridization, CRE mutant reporter assay, ChIP-like analysis The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 21653853
2013 NRG1 (ErbB2 ligand) inhibits GDNF-induced neuronal differentiation of mouse neural crest cells (enteric neuron precursors), while GDNF negatively regulates NRG1 signaling by down-regulating ErbB2 expression, establishing a functional interaction between RET/GDNF and NRG1/ERBB2 pathways in enteric nervous system development. Primary neural crest cell culture, neuronal differentiation assay, ErbB2 expression analysis after GDNF treatment Human genetics Medium 23400839
2014 CD74-NRG1 gene fusion leads to extracellular expression of the EGF-like domain of NRG1 III-β3, providing the ligand for ERBB2-ERBB3 receptor complexes. Ectopic expression of CD74-NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K-AKT pathway, and promoted anchorage-independent colony formation. Transcriptome sequencing, ectopic expression in cell lines, receptor phosphorylation assays, soft agar colony formation assay Cancer discovery High 24469108
2014 NRG1 activates NR2B (GluN2B) phosphorylation through ErbB4, and TrkB interacts with ErbB4 (shown by co-immunoprecipitation and proximity ligation assay); this TrkB-ErbB4 interaction increases upon NRG1 treatment. TrkB inhibition (K252a, siRNA, TrkB-/- neurons) suppresses NRG1-induced NR2B activation. NRG1-induced BDNF release (via GABAAR-TrkB) mediates phospho-TrkB and phospho-NR2B increases; BDNF neutralization abolishes these effects. Co-immunoprecipitation, proximity ligation assay, TrkB siRNA/knockout neurons, pharmacologic inhibition (K252a, AG1478), BDNF neutralization Cell communication and signaling : CCS High 25052836
2014 NRG1-ErbB4 signaling in the basolateral amygdala (BLA) modulates anxiety-like behaviors and GABA release but has no effect on glutamatergic transmission. ErbB4 is expressed almost exclusively in GABAergic neurons in the BLA; NRG1 administration into BLA alleviates anxiety and enhances GABAergic neurotransmission. Stereotactic NRG1 injection into BLA, electrophysiology (GABA release measurement), behavioral anxiety tests Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Medium 25308353
2015 CD74-NRG1 expression activates ErbB2/3 phosphorylation, PI3K/Akt/NF-κB signaling, and promotes cancer stem cell-like properties. NF-κB-dependent IGF2 expression and IGF1R phosphorylation are enhanced in CD74-NRG1-expressing cells, creating an IGF2 autocrine/paracrine circuit. Inhibition of ErbB2, PI3K, NF-κB, or IGF2 suppresses CD74-NRG1-induced tumor sphere formation. Ectopic expression, phospho-receptor/pathway assays, sphere formation assay, limiting dilution xenograft, pharmacologic inhibition Cancer research High 26837769
2015 DISC1 inhibits NRG1-induced ErbB4 activation and signaling in cortical interneurons; this inhibition is likely mediated by competitive inhibition of ErbB4 binding to PSD95. Cell-type-specific modulation of DISC1 in vitro and in vivo (including mutant DISC1 mouse model) demonstrated that DISC1 affects NRG1-ErbB4-mediated phenotypes in fast-spiking interneuron-pyramidal neuron circuits. Cell-type-specific gene modulation in vitro/in vivo, mutant DISC1 knock-in mouse, ErbB4/PSD95 binding competition assay, electrophysiology Nature communications High 26656849
2015 Paracrine NRG1 from fibroblasts activates ERBB3 on uveal melanoma cells and provides resistance to MEK inhibitor trametinib; ERBB3 inhibition combined with MEK inhibition overcomes this resistance. Trametinib treatment enhances responsiveness to NRG1. AKT inhibition reverses the NRG1-mediated protective effect. Conditioned medium experiments, ERBB3/cMET inhibitor experiments, xenograft models, AKT inhibition rescue Cancer research Medium 25952648
2016 A RET-ER81-NRG1 signaling pathway in mechanosensory neurons is required for Pacinian corpuscle formation. ER81 is required downstream of RET for maintaining interaction with nonmyelinating Schwann cells; ER81 loss reduces NRG1 isoform expression (specifically the isoform not involved in myelination). Ablating Nrg1 in mechanosensory neurons eliminates Pacinian corpuscles, establishing a distinct NRG1 isoform-dependent pathway for axon-nonmyelinating Schwann cell communication. Genetic ablation (Er81 mutant, Nrg1 conditional knockout in neurons), Pacinian corpuscle histology, isoform-specific expression analysis The Journal of neuroscience : the official journal of the Society for Neuroscience High 27707970
2015 VAMP2-NRG1 fusion gene is membrane-bound, displays the NRG1 EGF-like domain extracellularly, and promotes anchorage-independent colony formation in lung adenocarcinoma cells. Ectopic VAMP2-NRG1 expression stimulates phosphorylation of ERBB2, ERBB3, AKT, and ERK, confirming ERBB2/ERBB3 pathway activation as oncogenic mechanism. Whole-transcriptome sequencing, RT-PCR, immunoblotting, soft agar colony formation assay Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Medium 26134228
2017 Spironolactone acts as an antagonist of NRG1-ERBB4 signaling; it inhibits ERBB4 receptor phosphorylation and reverts cortical ERBB4 hyperphosphorylation in Nrg1 type III transgenic mice. Spironolactone increases spontaneous inhibitory postsynaptic currents in cortical slices, supporting ERBB4-mediated mode of action. Cell-based split TEV assay (compound screen), ERBB4 phosphorylation assay in transgenic mice, electrophysiology (cortical slice sIPSCs), behavioral tests EMBO molecular medicine High 28743784
2017 NRG1 regulates Fra-1 expression and TNBC metastasis via the ERK1/2-Fbxw7-c-Myc pathway: NRG1 activates ERK1/2, which phosphorylates Fbxw7 and promotes its dissociation and nuclear import of c-Myc; c-Myc then drives Fra-1 transcription. NRG1 knockdown suppresses TNBC cell metastasis and Fra-1 downregulation. NRG1 knockdown, ERK1/2 activation assays, ubiquitination assays (Fbxw7-c-Myc), ChIP (c-Myc on Fra-1 promoter), metastasis assays Oncogene Medium 34992218
2018 NRG1 fusions in pancreatic ductal adenocarcinoma (e.g., ATP1B1-NRG1, RBPMS-NRG1) drive ERBB receptor-mediated signaling. Pharmacologic ERBB inhibition (afatinib) resulted in clinical remission, functionally validating NRG1 fusions as ERBB pathway-activating oncogenic drivers in KRAS wild-type PDAC. Whole-genome and transcriptome sequencing, clinical ERBB inhibitor treatment with imaging response Cancer discovery Medium 29802158
2018 NRG1-Fc (NRG1 fused to IgG1 Fc) triggers potent AKT activation in the liver, lowers blood glucose, improves insulin sensitivity, and suppresses food intake in obese mice. NRG1-Fc acts as a FGF21 secretagogue; however, FGF21 is largely dispensable for its metabolic effects. NRG1-Fc directly targets hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. NRG1-Fc fusion protein engineering, AKT phosphorylation assays, FGF21 neutralization, electrophysiology of POMC neurons, metabolic measurements in obese mice JCI insight High 29515030
2018 NOTCH1 signaling promotes ECM degradation during trabeculation while NRG1 promotes myocardial ECM synthesis, necessary for trabecular rearrangement and growth. NRG1 controls Vegfa expression, interconnecting the two systems that act antagonistically to establish trabecular architecture. These epistatic relationships were established using cardiac-specific mutant mouse models. Cardiac-specific mutant mouse models, confocal imaging, transcriptomic analysis, ECM quantification Nature High 29743679
2019 NRG1/HER3 axis mediates ERBB3 activation by pancreatic cancer-associated fibroblasts (CAFs) and tumor cells; the anti-NRG1 antibody 7E3 blocks NRG1-mediated HER3 activation, promotes ADCC in NRG1-positive cells, and inhibits pancreatic cancer cell migration and growth co-cultured with CAFs both in vitro and in vivo in orthotopic xenografts. Anti-NRG1 antibody blocking, ADCC assays, co-culture migration/growth assays, orthotopic xenograft model Cancer letters Medium 29935372
2020 Nedd4l (E3 ubiquitin ligase) ubiquitinates NRG1 in the medial prefrontal cortex (mPFC) of stress-susceptible mice, reducing NRG1 protein levels without changing mRNA. Overexpression of Nedd4l in mPFC decreases NRG1 and causes stress vulnerability; downregulation of Nedd4l rescues NRG1 levels and attenuates depression-like behaviors. Ubiquitination assay, viral vector-mediated overexpression/knockdown, chronic social defeat stress model, RNA sequencing Translational psychiatry High 32703967
2021 Dysfunctional ERBB3 or ERBB2 mutations (identified by trio-exome sequencing) cause reduced expression or altered phosphorylation of the mutant receptors (confirmed by RT-qPCR and immunoblot), leading to a developmental syndrome including HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Single-cell RNA-seq and conditional ErbB3-deficient mouse models revealed a primary role for ERBB3 in enteric progenitors, establishing NRG1/ERBB3/ERBB2 signaling as essential for enteric nervous system development. Trio-exome sequencing, RT-qPCR on patient fibroblasts, immunoblot of mutant proteins, mouse scRNA-seq, conditional ErbB3 knockout mouse The Journal of clinical investigation High 33497358
2021 CAF-derived NRG1 activates cancer cell ERBB2 and ERBB3 receptor tyrosine kinases to support KRAS*-independent growth in PDAC. Genetic extinction or pharmacological inhibition of KRAS* upregulates ERBB2 and ERBB3 expression. Genetic depletion or pharmacological inhibition of ERBB2/3 or NRG1 abolishes KRAS* bypass and synergizes with KRASG12D inhibitors. Genetic depletion/pharmacologic inhibition of ERBB2/3 and NRG1 in mouse and human PDAC models, KRAS* extinction models, combination drug studies Genes & development High 37775182
2021 NRG1 regulates redox homeostasis in papillary thyroid cancer cells through the ERK pathway and NRF2, maintaining moderate ROS levels via ARE-containing antioxidant genes. NRG1 knockdown reduces cell viability and increases ROS, while NRG1 expression positively correlates with NRF2 in patient samples. NRG1 knockdown, ROS generation assay, intracellular GSH assay, Western blot for ERK/NRF2, CCK-8 assay International journal of oncology Medium 29901070
2022 Zenocutuzumab (bispecific anti-HER2×HER3 antibody) blocks NRG1 binding to HER3, inhibiting HER3 and AKT phosphorylation, inducing apoptosis markers, and inhibiting growth in NRG1 fusion-positive isogenic and patient-derived cell lines and xenograft models. This establishes that NRG1 fusions signal through HER3-HER2 heterodimerization as the primary oncogenic mechanism. Bispecific antibody blocking, phospho-HER3/AKT assays, apoptosis assays, PDX xenograft models, clinical response in patients Cancer discovery High 35135829
2022 NRG1 fusions can stimulate downstream signaling through HER4 independently of other HER family members, and EGFR-HER3 signaling is also activated; pan-HER inhibition is more effective than selective HER2-HER3 targeting. Cetuximab (anti-EGFR) plus trastuzumab/pertuzumab (anti-HER2) yielded synergistic effects against NRG1 fusion-positive cells. Ba/F3 models engineered with individual HER family members plus NRG1 fusions, receptor phosphorylation assays, combination drug synergy assays, in vivo models Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer High 37678511
2022 M2-like macrophage-derived Nrg1 signals through ErbB2 and ErbB4 on cardiac fibroblasts via PI3K/Akt pathway to suppress hydrogen peroxide-induced senescence and apoptosis of fibroblasts in infarcted myocardium. Blockade of ErbB function accelerates both fibroblast senescence/apoptosis and exacerbates inflammation. This Nrg1/ErbB/PI3K/Akt anti-senescence mechanism regulates post-MI fibrotic tissue formation. M2 macrophage isolation and co-culture, ErbB pharmacologic blockade, senescence/apoptosis assays, in vivo MI model with ErbB blockade FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 34997943
2022 NRG1-ERBB3-mTORC2 signaling drives acinar specification in salivary glands: neuronal NRG1 activates epithelial ERBB3 to trigger lineage progression, secretion, and polarization of acinar progenitors via mTORC2. Genetic deletion of Erbb3 prevents acinar lineage progression and lumenized secretory acini formation; exogenous NRG1 treatment of isolated epithelia recapitulates acinar development. Single-cell RNA sequencing, Erbb3 conditional knockout, NRG1 treatment of isolated epithelia, mTORC2 pathway analysis Developmental cell High 36413949
2023 Endocardial Nrg1 signals to myocardial ErbB2 to activate phospho-Erk, which regulates a transcriptional program for cardiomyocyte oriented cell division, trabeculation, and epithelial-to-mesenchymal transition-like migration. Loss of Nrg1 reduces cardiomyocyte Pard3 and Crumbs2 protein and alters cytoskeletal gene expression; ectopic Nrg1 overexpression causes S-phase arrest and prolonged trabeculation. Nrg1-dependent pErk activation controls Yap1 nuclear-cytoplasmic distribution. Cardiac-specific Nrg1 conditional knockout and overexpression mice, confocal imaging, transcriptomics, biochemical pErk/Yap1 assays Circulation research High 37846569
2025 Zenocutuzumab, a HER2×HER3 bispecific antibody that blocks NRG1 binding to HER3, produced objective responses in 30% of patients with NRG1 fusion-positive solid tumors across 12 tumor types, confirming that NRG1 fusions drive oncogenesis through HER3-HER2 heterodimerization as the primary mechanism. Phase 2 registrational clinical trial with objective response assessment The New England journal of medicine High 39908431

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. The EMBO journal 561 8617201
1996 GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron 322 8780647
1997 Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. Development (Cambridge, England) 287 9342043
2014 CD74-NRG1 fusions in lung adenocarcinoma. Cancer discovery 238 24469108
1993 Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER-2 suggests complex ligand-receptor relationships. The EMBO journal 229 8096177
2019 A Coevolved EDS1-SAG101-NRG1 Module Mediates Cell Death Signaling by TIR-Domain Immune Receptors. The Plant cell 224 31311833
2010 Nrg1/ErbB signaling networks in Schwann cell development and myelination. Seminars in cell & developmental biology 205 20832498
2018 NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer. Cancer discovery 200 29802158
2019 Diverse NLR immune receptors activate defence via the RPW8-NLR NRG1. The New phytologist 193 30582759
2019 Detection of NRG1 Gene Fusions in Solid Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 184 30988082
2002 Snf1 protein kinase and the repressors Nrg1 and Nrg2 regulate FLO11, haploid invasive growth, and diploid pseudohyphal differentiation. Molecular and cellular biology 174 12024013
2006 Association of the NRG1 gene and schizophrenia: a meta-analysis. Molecular psychiatry 173 16520822
2018 Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation. Nature 169 29743679
2022 Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements. Cancer discovery 146 35135829
2021 Pathogen effector recognition-dependent association of NRG1 with EDS1 and SAG101 in TNL receptor immunity. Nature communications 137 34099661
2014 Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes. Nature communications 137 25531467
2011 Specific regulation of NRG1 isoform expression by neuronal activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 136 21653853
2020 NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Annals of oncology : official journal of the European Society for Medical Oncology 134 32916265
2019 NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 131 31068372
1997 ErbB kinases and NDF signaling in human prostate cancer cells. Oncogene 128 9400997
1995 NDF/heregulin activates MAP kinase and p70/p85 S6 kinase during proliferation or differentiation of mammary epithelial cells. Oncogene 112 7824269
1997 Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation. Oncogene 107 9419971
1996 Effects of GGF/neuregulins on neuronal survival and neurite outgrowth correlate with erbB2/neu expression in developing rat retina. Development (Cambridge, England) 107 8625831
2025 Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer. The New England journal of medicine 90 39908431
1999 GGF/neuregulin induces a phenotypic reversion of oligodendrocytes. Molecular and cellular neurosciences 88 10192767
2014 Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 77 25501131
2009 NRG1 / ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. Pigment cell & melanoma research 71 19659570
1994 NDF/heregulin stimulates the phosphorylation of Her3/erbB3. FEBS letters 70 8045292
2014 Amygdala NRG1-ErbB4 is critical for the modulation of anxiety-like behaviors. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 69 25308353
2015 Activation of NRG1-ERBB4 signaling potentiates mesenchymal stem cell-mediated myocardial repairs following myocardial infarction. Cell death & disease 67 25996292
1997 Schwann cells express NDF and SMDF/n-ARIA mRNAs, secrete neuregulin, and show constitutive activation of erbB3 receptors: evidence for a neuregulin autocrine loop. Experimental neurology 65 9417836
2009 Erbin regulates NRG1 signaling and myelination. Proceedings of the National Academy of Sciences of the United States of America 64 19458253
2019 Detection of Novel NRG1, EGFR, and MET Fusions in Lung Adenocarcinomas in the Chinese Population. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 61 31382039
2005 Composite PHB-GGF conduit for long nerve gap repair: a long-term evaluation. Scandinavian journal of plastic and reconstructive surgery and hand surgery 60 16019744
2005 Repressors Nrg1 and Nrg2 regulate a set of stress-responsive genes in Saccharomyces cerevisiae. Eukaryotic cell 60 16278455
2015 Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma. Cancer research 59 25952648
2015 Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. Nature communications 59 26656849
2017 IGF1 and NRG1 Enhance Proliferation, Metabolic Maturity, and the Force-Frequency Response in hESC-Derived Engineered Cardiac Tissues. Stem cells international 58 28951744
2016 Oncogenic Fusion Gene CD74-NRG1 Confers Cancer Stem Cell-like Properties in Lung Cancer through a IGF2 Autocrine/Paracrine Circuit. Cancer research 57 26837769
2019 Mechanisms of the Multitasking Endothelial Protein NRG-1 as a Compensatory Factor During Chronic Heart Failure. Circulation. Heart failure 54 31607147
2010 LH-induced neuregulin 1 (NRG1) type III transcripts control granulosa cell differentiation and oocyte maturation. Molecular endocrinology (Baltimore, Md.) 54 21047912
2020 Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series. The oncologist 50 32852072
2018 Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer. Cancer letters 47 29935372
1998 Chronically denervated rat Schwann cells respond to GGF in vitro. Glia 47 9775980
2022 NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis. Trends in cancer 44 34996744
2013 RET and NRG1 interplay in Hirschsprung disease. Human genetics 41 23400839
2024 The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions. Future oncology (London, England) 39 38348690
2022 Nrg1/ErbB signaling-mediated regulation of fibrosis after myocardial infarction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 34997943
2018 NRG1-Fc improves metabolic health via dual hepatic and central action. JCI insight 38 29515030
2023 Nrg1 Regulates Cardiomyocyte Migration and Cell Cycle in Ventricular Development. Circulation research 36 37846569
2018 NDF, a nucleosome-destabilizing factor that facilitates transcription through nucleosomes. Genes & development 36 29759984
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
2017 Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice. EMBO molecular medicine 36 28743784
2015 VAMP2-NRG1 Fusion Gene is a Novel Oncogenic Driver of Non-Small-Cell Lung Adenocarcinoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 35 26134228
2021 Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans. The Journal of clinical investigation 33 33497358
2020 The role of endothelial autocrine NRG1/ERBB4 signaling in cardiac remodeling. American journal of physiology. Heart and circulatory physiology 33 32618511
2009 DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study. Neuropsychobiology 32 19439994
2020 CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer's disease. Alzheimer's research & therapy 31 32690068
2018 Astraglaus polysaccharide protects diabetic cardiomyopathy by activating NRG1/ErbB pathway. Bioscience trends 31 29607874
2023 Effector XopQ-induced stromule formation in Nicotiana benthamiana depends on ETI signaling components ADR1 and NRG1. Plant physiology 30 36259930
2022 Role of the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats. Inflammopharmacology 30 35876932
2017 Elevated peripheral expression of neuregulin-1 (NRG1) mRNA isoforms in clozapine-treated schizophrenia patients. Translational psychiatry 30 29225331
2021 Prrx1b restricts fibrosis and promotes Nrg1-dependent cardiomyocyte proliferation during zebrafish heart regeneration. Development (Cambridge, England) 29 34486669
2022 MOTS-c and Exercise Restore Cardiac Function by Activating of NRG1-ErbB Signaling in Diabetic Rats. Frontiers in endocrinology 28 35370955
2021 Neuregulin 1 Gene (NRG1). A Potentially New Targetable Alteration for the Treatment of Lung Cancer. Cancers 28 34680187
2017 Increased NRG1-ErbB4 signaling in human symptomatic epilepsy. Scientific reports 28 28273943
2017 NRG1-ErbB Lost in Translation: A New Paradigm for Lung Cancer? Current medicinal chemistry 28 28901268
2017 The acceleration of reproductive aging in Nrg1flox/flox ;Cyp19-Cre female mice. Aging cell 27 28857490
2016 A RET-ER81-NRG1 Signaling Pathway Drives the Development of Pacinian Corpuscles. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 27707970
2022 NRG1 regulates Fra-1 transcription and metastasis of triple-negative breast cancer cells via the c-Myc ubiquitination as manipulated by ERK1/2-mediated Fbxw7 phosphorylation. Oncogene 26 34992218
2018 The Role of NRG1 in the Predisposition to Papillary Thyroid Carcinoma. The Journal of clinical endocrinology and metabolism 24 29121253
2021 NRG1 fusions in breast cancer. Breast cancer research : BCR 23 33413557
2023 Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer. Genes & development 22 37775182
2020 Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice. Translational psychiatry 22 32703967
2021 Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts. Oncogene 21 33692466
2021 NRG1/ErbB signalling controls the dialogue between macrophages and neural crest-derived cells during zebrafish fin regeneration. Nature communications 21 34732706
2019 lncRNA CASC9 regulates cell migration and invasion in hemangioma endothelial cells by targeting miR-125a-3p/Nrg1. OncoTargets and therapy 21 30662268
2021 NRG1 fusions: Biology to therapy. Lung cancer (Amsterdam, Netherlands) 20 34098222
1998 Predicting forage indigestible NDF from lignin concentration. Journal of animal science 20 9621956
2024 Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma. Cancer research 19 38175774
2020 Ranolazine protects against diabetic cardiomyopathy by activating the NOTCH1/NRG1 pathway. Life sciences 19 32828943
2023 HER4 and EGFR Activate Cell Signaling in NRG1 Fusion-Driven Cancers: Implications for HER2-HER3-specific Versus Pan-HER Targeting Strategies. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 18 37678511
2021 Roles and mechanisms of NRG1 in modulating the pathogenesis of NAFLD through ErbB3 signaling in hepatocytes (NRG1 modulates NAFLD through ErbB3 signaling). Obesity research & clinical practice 18 33541789
2019 Nrg1 Intracellular Signaling Is Neuroprotective upon Stroke. Oxidative medicine and cellular longevity 18 31583038
2014 TrkB interacts with ErbB4 and regulates NRG1-induced NR2B phosphorylation in cortical neurons before synaptogenesis. Cell communication and signaling : CCS 18 25052836
2011 Expression of NRG1 and its receptors in human bladder cancer. British journal of cancer 18 21364580
2019 MCLA-128 Fights NRG1 Fusion-Positive Cancers. Cancer discovery 17 31685488
2003 Effects of corn silage hybrid and dietary concentration of forage NDF on digestibility and performance by dairy cows. Journal of dairy science 17 14672197
2022 Oncogenic Neuregulin 1 gene (NRG1) fusions in cancer: A potential new therapeutic opportunities. Biochimica et biophysica acta. Reviews on cancer 16 35247506
2012 Aberrant high expression of NRG1 gene in Hirschsprung disease. Journal of pediatric surgery 16 22974608
2025 The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury. Redox biology 15 39874927
2022 NRG1/ERBB3/ERBB2 Axis Triggers Anchorage-Independent Growth of Basal-like/Triple-Negative Breast Cancer Cells. Cancers 15 35406375
2021 NFKB2 inhibits NRG1 transcription to affect nucleus pulposus cell degeneration and inflammation in intervertebral disc degeneration. Mechanisms of ageing and development 15 34023356
2018 NRG1 regulates redox homeostasis via NRF2 in papillary thyroid cancer. International journal of oncology 15 29901070
2018 NRG1 variant effects in patients with Hirschsprung disease. BMC pediatrics 15 30180823
2015 Polymorphisms of dopamine pathway genes NRG1 and LMX1A are associated with cognitive performance in bipolar disorder. Bipolar disorders 15 26534905
2022 Neuronal-epithelial cross-talk drives acinar specification via NRG1-ERBB3-mTORC2 signaling. Developmental cell 14 36413949
2014 NRG1-ErbB signalling promotes microglia activation contributing to incision-induced mechanical allodynia. European journal of pain (London, England) 14 25159022
2013 The expression and localization of neuregulin-1 (Nrg1) in the gastrointestinal system of the rhesus monkey. Folia histochemica et cytobiologica 14 23690216
2023 RNA Sequencing Identifies Novel NRG1 Fusions in Solid Tumors that Lack Co-Occurring Oncogenic Drivers. The Journal of molecular diagnostics : JMD 12 37164276

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