Affinage

NRG1

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

Round 2 corrected
Length
640 aa
Mass
70.4 kDa
Annotated
2026-04-29
130 papers in source corpus 53 papers cited in narrative 51 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRG1 encodes a family of alternatively spliced EGF-like growth factors that signal primarily through ErbB3 (HER3) and ErbB4 (HER4) receptors, which heterodimerize with ErbB2 (HER2) to activate PI3K-AKT, MAPK/ERK, and SAPK/JNK cascades, governing cell proliferation, survival, differentiation, and myelination across neural, cardiac, epithelial, and metabolic tissues (PMID:1350381, PMID:7514177, PMID:8617201, PMID:9019162). Distinct NRG1 isoforms (Types I–VI) generated by alternative promoter usage and splicing serve non-redundant developmental functions: Type III NRG1 drives Schwann cell development and peripheral myelination, Type I is required for cranial ganglia formation and cardiac trabeculation—where endocardial NRG1 activates myocardial ErbB2–pERK–Yap1 signaling to orient cardiomyocyte division—and activity-dependent Type I/IV expression is controlled by CREB-dependent transcription in neurons (PMID:9342050, PMID:37846569, PMID:21653853). NRG1–ErbB4 signaling modulates NMDA receptor function via ErbB4–PSD95 interactions in cortical interneurons, and NRG1 hypomorphic mice exhibit reduced NMDA receptors and schizophrenia-relevant behavioral phenotypes partially reversible by clozapine, establishing NRG1 as a schizophrenia susceptibility gene (PMID:12145742, PMID:16767099). Oncogenic NRG1 gene fusions constitutively present the EGF-like domain at the cell surface to activate HER2–HER3 (and HER4/EGFR) heterodimers, while cancer-associated fibroblast-derived paracrine NRG1 confers resistance to KRAS, MEK, and FGFR inhibitors through sustained ERBB3–AKT signaling (PMID:35135829, PMID:37775182, PMID:38175774).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1992 High

    Identification of NRG1 as the activating ligand of the ErbB2 receptor tyrosine kinase resolved the long-standing question of what physiological signal triggers p185erbB2 phosphorylation.

    Evidence Protein purification from conditioned medium with Scatchard binding and chemical cross-linking in two independent studies

    PMID:1348215 PMID:1350381

    Open questions at the time
    • Direct receptor (ErbB3/ErbB4) had not yet been identified as the primary binding partner
    • Downstream signaling pathways not yet mapped
  2. 1994 High

    Reconstitution of the ErbB2–ErbB3 heterodimer as the high-affinity NRG1 receptor established that ErbB2 is not the direct ligand-binding subunit but rather a co-receptor that amplifies signaling through transphosphorylation, while isoform diversity (GGF/heregulin/SMDF) was shown to arise from alternative splicing of a single gene.

    Evidence ErbB2/ErbB3 co-transfection with Scatchard analysis, cross-linking, kinase-dead mutagenesis establishing transphosphorylation directionality; cDNA cloning of GGF isoforms

    PMID:7514177 PMID:7556068 PMID:8096067

    Open questions at the time
    • Relative contributions of ErbB4 vs ErbB3 in different tissues unclear
    • Structural basis of heterodimer formation unknown
  3. 1996 High

    Demonstration that ErbB2 functions as a pan-ErbB auxiliary subunit by decelerating ligand dissociation—and that NRG1 drives oligodendrocyte proliferation/survival and radial glial maintenance—broadened NRG1's role from a receptor activator to a pleiotropic neural growth factor.

    Evidence ErbB2 overexpression/surface-depletion with kinetic binding analysis; oligodendrocyte culture with antibody blocking and ErbB receptor phosphorylation; ErbB2 knockout and cortical development analysis in mice

    PMID:8617201 PMID:8780647 PMID:9342043

    Open questions at the time
    • Mechanism by which NRG1 controls radial glial vs neuronal targets not separated at isoform level
    • In vivo relevance of ErbB2 kinetic modulation not yet demonstrated genetically
  4. 1997 High

    Isoform-specific gene targeting revealed that Type I and Type III NRG1 have non-redundant functions—Type I in cranial ganglia and cardiac trabeculation, Type III in Schwann cell development—demonstrating that alternative splicing generates functionally distinct signaling molecules.

    Evidence Targeted isoform-specific mutations in mice with histological analysis of distinct developmental phenotypes

    PMID:9342050

    Open questions at the time
    • Type IV, V, VI isoform functions not yet characterized
    • Molecular basis for isoform-specific receptor engagement unknown
  5. 2002 High

    Linkage and association studies identified NRG1 as a schizophrenia susceptibility locus, and NRG1 hypomorphic mice showed reduced NMDA receptors and clozapine-reversible behavioral phenotypes, connecting NRG1 to synaptic glutamate signaling.

    Evidence Genome-wide linkage scan, haplotype association, NRG1 hypomorph mice with NMDA receptor quantification and pharmacological rescue

    PMID:12145742 PMID:12478479

    Open questions at the time
    • Causal variants within the NRG1 locus not identified
    • Whether NRG1-ErbB4 directly regulates NMDA receptor trafficking or function was unresolved
  6. 2006 High

    Postmortem studies established that NRG1-induced ErbB4 hyperactivation and enhanced ErbB4–PSD95 interaction suppress NMDA receptor activation in schizophrenia prefrontal cortex, providing a molecular mechanism for NMDA hypofunction; disease-associated SNPs were shown to regulate isoform-specific expression including the novel Type IV isoform.

    Evidence Postmortem tissue NRG1 stimulation with ErbB4 phosphorylation and PSD95 co-IP; quantitative RT-PCR genotype-expression correlation in hippocampus

    PMID:16618933 PMID:16767099

    Open questions at the time
    • Whether PSD95–ErbB4 interaction is the primary mechanism of NRG1-induced NMDA suppression in vivo
    • Functional validation of SNP-altered transcription factor binding sites lacking
  7. 2009 High

    NRG1–ErbB4 signaling was shown to drive mononucleated cardiomyocyte proliferation and promote myocardial regeneration after infarction, while Erbin was identified as a PDZ-domain adaptor required for ErbB2 stability and NRG1-dependent peripheral myelination.

    Evidence ErbB4 genetic knockout/overexpression with NRG1 injection and lineage tracing in adult mice; Erbin knockout and PDZ-deleted knockin mice with nerve histology and ErbB2 stability assays

    PMID:19458253 PMID:19632177

    Open questions at the time
    • Why only mononucleated cardiomyocytes respond to NRG1 is mechanistically unexplained
    • Whether Erbin functions similarly in CNS myelination unknown
  8. 2014 High

    Direct transcriptional activation of NRG1 by p63 in mammary basal cells established a basal-to-luminal paracrine axis (NRG1→ERBB4→STAT5A) essential for lactation, revealing cell-type-specific transcriptional control of NRG1 with defined physiological consequences.

    Evidence Conditional p63 knockout in adult mammary basal cells, ChIP for p63 at Nrg1 promoter, ERBB4/STAT5A phosphorylation, functional lactation assay

    PMID:24412575

    Open questions at the time
    • Whether other NRG1 isoforms contribute to mammary development not assessed
    • Mechanism of STAT5A activation by ERBB4 in this context not fully dissected
  9. 2019 High

    Characterization of NRG1 gene fusions (CD74-, SLC3A2-, ATP1B1-NRG1) revealed that chimeric proteins constitutively present the EGF-like domain on the cell surface to activate HER2–HER3 heterodimers and PI3K-AKT/MAPK signaling; ADAM17-mediated shedding of fusion NRG1 was later shown to be enhanced by KRAS-MEK-ERK signaling.

    Evidence RNA sequencing for fusion detection, ERBB2/3 phosphorylation assays, zenocutuzumab blocking, ADAM17 activity assays, xenograft models

    PMID:29959202 PMID:34743207 PMID:35135829

    Open questions at the time
    • Clinical efficacy of NRG1 fusion-targeted therapies not established
    • Structural basis for constitutive activation by different fusion partners not resolved
  10. 2020 Medium

    NRG1 protein stability was shown to be regulated by Nedd4l-mediated ubiquitination in the prefrontal cortex, linking NRG1 degradation to stress vulnerability and depression-like phenotypes and revealing a post-translational control mechanism.

    Evidence Ubiquitination assays, Nedd4l overexpression/knockdown via viral vectors, CSDS behavioral model

    PMID:32703967

    Open questions at the time
    • Whether Nedd4l targets specific NRG1 isoforms is unknown
    • Ubiquitination sites on NRG1 not mapped
    • Independent replication in a second behavioral paradigm lacking
  11. 2023 High

    CAF-secreted NRG1 was identified as a KRAS*-independent survival mechanism in pancreatic cancer: KRAS extinction upregulates ERBB2/3 expression, enabling NRG1-driven bypass; paracrine NRG1 from adipocyte precursors similarly confers resistance to FGFR inhibitors, establishing NRG1–ERBB3 as a general therapeutic resistance axis.

    Evidence KRAS conditional extinction with NRG1 genetic depletion in CAFs, ERBB2/3 inhibition in PDAC models; co-culture with adipocyte precursors, NRG1 knockdown, pertuzumab reversal in xenografts

    PMID:37775182 PMID:38175774

    Open questions at the time
    • Whether NRG1-mediated resistance generalizes across all KRAS-mutant cancers untested
    • Direct clinical validation of combination strategies pending
  12. 2023 High

    An endocardial NRG1–myocardial ErbB2–pERK–Yap1 axis was shown to orient cardiomyocyte cell division and regulate polarity proteins (Pard3, Crumbs2) during trabeculation, unifying earlier genetic observations into a coherent morphogenetic signaling cascade.

    Evidence Cardiac-specific Nrg1 knockout and overexpression with confocal imaging of division orientation, pERK and polarity protein analysis, Yap1 localization

    PMID:37846569

    Open questions at the time
    • How pERK regulates Yap1 nuclear-cytoplasmic distribution mechanistically unresolved
    • Whether Pard3/Crumbs2 are direct or indirect pERK targets unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for isoform-specific receptor selectivity, the full spectrum of NRG1 isoform functions in the adult brain, and the clinical impact of targeting the NRG1–ERBB axis in NRG1 fusion-driven cancers and therapy resistance settings.
  • No high-resolution structure of NRG1 isoform-specific receptor complexes
  • Type V and VI isoform functions remain uncharacterized
  • Clinical trial results for NRG1 fusion-targeted therapies not yet in primary literature

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 5 GO:0005886 plasma membrane 4
Pathway
R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4
Partners
ADAM17ERBB2ERBB3ERBB4ERBINNEDD4LPSD95

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 NRG1 (heregulin/NDF) was purified as a 44-45 kDa glycoprotein ligand that specifically induces phosphorylation of p185erbB2/Neu receptor at picomolar concentrations, establishing NRG1 as the activating ligand for the ErbB2 receptor tyrosine kinase. Protein purification from conditioned medium, Scatchard binding analysis, chemical cross-linking with radiolabeled ligand, immunoprecipitation Science / Cell High 1348215 1350381
1993 Glial growth factors (GGF), mitogenic proteins for Schwann cells, are alternatively spliced isoforms of NRG1 and act as ligands for p185erbB2 receptor, with alternative splicing generating membrane-attached, intracellular and secreted signaling proteins. cDNA cloning, alternative splicing analysis, in situ hybridization, receptor binding assays Nature High 8096067
1993 NDF (NRG1) binds with high affinity (Kd ~10^-9 M) to mammary cells via a complex requiring both ErbB2/Neu and an additional cellular co-receptor; ovarian cells overexpressing Neu did not show covalent cross-linking to NDF and lacked NDF-induced PI3-kinase association, indicating cell-type-specific receptor requirements. Radiolabeled NDF cross-linking, monoclonal antibody blocking, direct binding analysis, PI3-kinase co-immunoprecipitation The EMBO journal High 8096177
1994 Co-expression of ErbB2 and ErbB3 reconstitutes a high-affinity heregulin (NRG1) binding receptor; ErbB3 alone binds heregulin with lower affinity and shows little tyrosine phosphorylation, whereas the ErbB2/ErbB3 heterodimer generates robust tyrosine phosphorylation signaling. Chemical cross-linking confirmed direct interaction of heregulin with both ErbB2 and ErbB3 in the heterodimer. Receptor transfection/reconstitution, Scatchard binding analysis, 125I-heregulin cross-linking, immunoprecipitation, tyrosine phosphorylation assays The Journal of biological chemistry High 7514177
1995 HRG (NRG1) beta2 stimulates tyrosine phosphorylation of ErbB2, ErbB3, and ErbB4 in breast cancer cells, induces formation of Shc-Grb2 complexes and receptor-Shc complexes, and stimulates PI3-kinase association with ErbB3, revealing multiple inputs into Ras signaling; ErbB3 associates with PI3-kinase but Grb2 associates with ErbB2 and ErbB4 but not ErbB3, indicating mechanistic differences in Ras coupling among ErbB receptors. Tyrosine phosphorylation assays, co-immunoprecipitation, PI3-kinase association assays, cell proliferation assays Cell growth & differentiation High 9019162
1995 NRG1 beta isoforms bind ErbB-3 directly (Kd = 2.2 nM) and exert mitogenic effects on keratinocytes, whereas alpha isoforms bind the same receptor with lower affinity and produce minimal mitogenesis, demonstrating that different NRG1 isoforms elicit distinct growth regulatory effects through differential binding affinity to ErbB-3. Radioligand binding assays, mitogenesis assays, RT-PCR for receptor expression, keratinocyte culture Oncogene High 7731691
1995 HRG (NRG1) induces HER2-HER3 heterodimerization; ATP-binding-site mutants demonstrate that HER2 transphosphorylates HER3 (but not vice versa), and HRG-induced HER3 transphosphorylation enhances SHC and PI3-kinase association and confers transforming activity to NIH 3T3 cells co-expressing HER2 and HER3. ATP-binding-site kinase-dead mutants, co-immunoprecipitation, NIH 3T3 transformation assay, PI3-kinase association assay The EMBO journal High 7556068
1996 ErbB-2 functions as a pan-ErbB auxiliary subunit by forming heterodimers with both ErbB-1 (EGFR) and NDF receptors (ErbB-3 and ErbB-4); ErbB-2 overexpression enhances binding affinities of both EGF and NDF by decelerating ligand dissociation rates, thereby prolonging and potentiating downstream ERK and SAPK/JNK signaling cascades. Removal of ErbB-2 from the cell surface almost completely abolished NDF binding. ErbB-2 overexpression, ER-trapped antibody to block cell surface delivery, kinetic binding analysis, co-immunoprecipitation, MAP kinase/JNK activity assays The EMBO journal High 8617201
1996 GGF/neuregulin (NRG1) acts as a mitogen for pro-oligodendrocytes and oligodendrocytes, promotes their survival under serum-free conditions, and at high concentrations reversibly inhibits differentiation and lineage commitment; all three ErbB receptors (ErbB2, ErbB3, ErbB4) are expressed by oligodendrocyte progenitors and are activated by GGF, with relative abundance changing during differentiation. Cortical neurons release a soluble GGF-like mitogen for pro-oligodendrocytes that is blocked by anti-GGF antibodies. Cell culture proliferation/survival assays, antibody blocking, Western blot for ErbB receptor phosphorylation, neuron-conditioned medium experiments Neuron High 8780647
1996 GGF/neuregulin (NRG1) is expressed by migrating cortical neurons and promotes their migration along radial glial fibers; concurrently, GGF promotes maintenance and elongation of radial glial cells via ErbB2 receptor signaling. In the absence of ErbB2-mediated GGF signaling, radial glial development is abnormal. GGF regulation of radial glial development is mediated in part by brain lipid-binding protein (BLBP). In vivo mouse cortical development analysis, antibody inhibition, ErbB2 knockout analysis, BLBP expression studies Development (Cambridge, England) High 9342043
1997 NRG1 isoform-specific functions in vivo: Type I neuregulin is required for generation of neural crest-derived neurons in cranial ganglia and for trabeculation of the heart ventricle, while Type III neuregulin plays an important role in early Schwann cell development, demonstrating that distinct NRG1 isoforms have non-redundant functions in development. Targeted isoform-specific gene mutations in mice, in situ hybridization, histological analysis of developmental phenotypes Development (Cambridge, England) High 9342050
1997 NDF (NRG1) signaling in prostate cancer cells via ErbB3/ErbB2 heterodimers (not ErbB1) activates PI3-K, ERK/MAPK, mHOG/p38, and JNK/SAPK pathways but not PLCγ or STAT signaling; ErbB3-PI3-K association forms a striking 'activation complex' with multiple tyrosine-phosphorylated species. NDF inhibits LNCaP growth and induces epithelial-like morphological change in contrast to TGF-α. Immunoprecipitation, Western blot for phosphorylation, PI3-K activation assays, proliferation assays Oncogene Medium 9400997
1997 Schwann cells express NDF and SMDF/n-ARIA NRG1 mRNAs, secrete neuregulin protein (~45 kDa), and show constitutive activation of ErbB3 receptor, demonstrating an autocrine neuregulin loop in Schwann cells. An anti-neuregulin antibody inhibits Schwann cell proliferation in response to neurons and also blocks proliferation induced by unrelated mitogens including bFGF, HGF, and TGF-β1, indicating that neuregulin autocrine signaling is a convergence point for multiple mitogenic signals. RT-PCR, ELISA for neuregulin secretion, ErbB3 activation assays, antibody blocking of proliferation Experimental neurology Medium 9417836
1997 Neuregulin-2 (NRG-2) is a distinct gene product (not NRG1) whose EGF-like domain binds ErbB3 and ErbB4; however, NRG-2 stimulates different ErbB-receptor tyrosine-phosphorylation profiles than NRG1, indicating that NRG1 and NRG-2 mediate distinct biological processes despite shared receptor binding. Ligand binding assays, receptor phosphorylation profiling, expression analysis Nature Medium 9168115
1998 NRG1 (as rhGGF2) promotes survival, inhibits apoptosis, and induces hypertrophic growth of neonatal and adult rat cardiac myocytes via ErbB2 and ErbB4 receptors expressed on these cells. NRG1 mRNA is produced by coronary microvascular endothelial cells and is upregulated by endothelin-1, establishing a paracrine endothelial-to-cardiomyocyte NRG1 signaling axis. Isolated cardiomyocyte cultures, proliferation/apoptosis assays, receptor phosphorylation, RT-PCR for NRG1 in endothelial cells, endothelin-1 stimulation The Journal of biological chemistry High 9553078
1999 MPA (progestin) induces HRG (NRG1) mRNA expression in mouse mammary tumor cells; antisense oligonucleotides to HRG inhibit MPA-induced cell growth, demonstrating HRG acts as a mediator of progestin-induced proliferation. Both HRG and MPA proliferative effects require ErbB-2 and a functional IGF-1 receptor. Antisense oligodeoxynucleotides, RT-PCR, tyrosine phosphorylation assays, proliferation assays Oncogene Medium 10597237
1999 In human ovarian carcinoma cells, NRG1 (HRG) activates HER3 independently of HER2 in some cell lines; EGF preferentially induces EGFR-HER2 heterodimers while HRG preferentially activates HER3/HER4 depending on receptor abundance; EGF and HRG mediate cell growth through distinct receptor complexes (EGFR/HER2 vs. HER4), while HER3 alone does not mediate growth even when phosphorylated. Receptor co-immunoprecipitation, phosphorylation assays, proliferation assays across cell lines with different receptor expression Journal of cellular biochemistry Medium 10733345
2002 NRG1 was identified as a susceptibility gene for schizophrenia by genome-wide linkage scan and haplotype-association analysis; NRG1 hypomorphic mice have fewer functional NMDA receptors, and ErbB4 receptor reduction produces behavioral phenotypes overlapping with mouse models of schizophrenia. The behavioral phenotypes of NRG1 hypomorphs are partially reversible with clozapine treatment. Genome-wide linkage scan, haplotype association, NRG1 hypomorph mouse behavioral analysis, NMDA receptor quantification, clozapine pharmacological rescue American journal of human genetics High 12145742 12478479
2003 In differentiated human airway epithelia, NRG1 (heregulin-alpha) is segregated exclusively to the apical membrane while its receptors ErbB2-4 localize to the basolateral membrane, physically separated by tight junctions. Upon mechanical injury, heregulin-alpha activates ErbB2 in cells at the wound edge, promoting restoration of epithelial integrity. This ligand-receptor segregation mechanism regulates NRG1/ErbB signaling. Confocal microscopy of polarized epithelia, mechanical injury assays, receptor phosphorylation after injury, tight junction manipulation Nature High 12646923
2005 αvβ3 integrin regulates NRG1 (HRG)-induced ERK1/2 MAPK activation and cell proliferation; HRG promotes αvβ3 expression through its downstream effector CYR61; blockade of αvβ3 impairs HRG-promoted ERK1/2 hyperactivation without altering AKT activation, and αvβ3 antagonists decrease S- and G2/M-phase subpopulations with increased p27Kip1 nuclear translocation. αvβ3 antagonists, antisense oligodeoxynucleotides, flow cytometry, ERK/AKT phosphorylation assays, p27Kip1 nuclear translocation Oncogene Medium 15782133
2006 In schizophrenia postmortem prefrontal cortex, NRG1-induced activation of ErbB4 is markedly increased compared to controls despite no change in NRG1 or ErbB4 protein levels. This hyperactivation correlates with substantially increased ErbB4-PSD95 interactions (PSD95 facilitates ErbB4 activation). NRG1 stimulation suppresses NMDA receptor activation in human prefrontal cortex, and this suppression is more pronounced in schizophrenia, suggesting NRG1-ErbB4 hyperactivation contributes to NMDA receptor hypofunction. Postmortem tissue stimulation with NRG1, ErbB4 phosphorylation assays, PSD95-ErbB4 co-immunoprecipitation, NMDA receptor activation measurement Nature medicine High 16767099
2006 Disease-associated SNPs in the 5' upstream region of NRG1 regulate mRNA expression of specific isoforms: SNP8NRG221132 interacts with schizophrenia diagnosis to affect Type I NRG1 (34% increase in schizophrenia), and SNP8NRG243177 within the risk haplotype is associated with expression of the novel Type IV NRG1 isoform. Bioinformatic analysis reveals these SNPs alter binding sites for SRF, MYT1, and HMG Box Protein-1 transcription factors. Quantitative RT-PCR of postmortem hippocampus, genotype-expression correlation, bioinformatic promoter analysis Proceedings of the National Academy of Sciences of the United States of America Medium 16618933
2007 Notch1 signaling in ventricular endocardium directly regulates EphrinB2 expression (a direct Notch transcriptional target), which acts upstream of NRG1 in trabeculation; NRG1 signaling mediates cardiomyocyte differentiation downstream of Notch-EphrinB2, while BMP10 independently regulates cardiomyocyte proliferation. RBPJk/Notch1 mutants show attenuated NRG1 expression and signaling. RBPJk and Notch1 mutant mice, NRG1 expression analysis, exogenous NRG1 rescue of differentiation defects in cultured RBPJk mutant hearts, luciferase reporter assays for EphrinB2 as Notch target Developmental cell High 17336907
2009 NRG1 induces mononucleated (but not binucleated) cardiomyocytes to proliferate via ErbB4 signaling; genetic inactivation of ErbB4 reduces cardiomyocyte proliferation while increased ErbB4 expression enhances it. Injection of NRG1 in adult mice induces cardiomyocyte cell-cycle activity and promotes myocardial regeneration, improving cardiac function after myocardial infarction without contribution from undifferentiated progenitor cells. ErbB4 genetic knockout/overexpression, NRG1 injection in adult mice, cardiomyocyte cell cycle analysis, post-infarction cardiac function measurement, cell lineage tracing Cell High 19632177
2009 NRG1/ERBB3 signaling inhibits melanocyte maturation and promotes undifferentiated, migratory, and proliferative characteristics; ERBB3 signaling was necessary and sufficient to inhibit differentiation of later-stage melanocytes in culture. NRG1-treated melanocytes showed increased proliferation, invasion, and altered morphology with decreased differentiation gene expression and increased proliferation/metastasis gene levels. ERBB3 knockout analysis in embryos, NRG1 treatment of cultured melanocytes, proliferation/invasion assays, gene expression profiling Pigment cell & melanoma research Medium 19659570
2009 Erbin, a protein with LRR and PDZ domains that interacts specifically with ErbB2, is necessary for NRG1 signaling and myelination of the peripheral nervous system. Erbin null mice show hypomyelination and aberrant unmyelinated axon ensheathing; Erbin's PDZ domain binds and stabilizes ErbB2, which is required for NRG1 signaling. Loss of Erbin destabilizes ErbB2 protein and compromises NRG1 signaling. Erbin knockout and PDZ-domain-deleted knockin mice, sciatic nerve histology, ErbB2 protein stability assays, nerve conduction velocity measurement, siRNA knockdown Proceedings of the National Academy of Sciences of the United States of America High 19458253
2010 LH induces expression of Type III NRG1 transcripts in granulosa cells in an ERK1/2 and C/EBPβ-dependent manner during ovulation. NRG1 binds ERBB3/ERBB2 complexes on granulosa and cumulus cells, selectively stimulates AKT/PKB phosphorylation over ERK1/2, and synergizes with amphiregulin (AREG) to enhance ERK1/2 phosphorylation, progesterone production, and oocyte developmental competence. Western blotting, granulosa cell culture, AKT/ERK phosphorylation assays, progesterone RIA, oocyte developmental competence assay, conditional ERK1/2 inhibition Molecular endocrinology Medium 21047912
2011 NRG1 isoform expression in the brain is regulated by neuronal activity; activity causes significant increases in Type I and Type IV NRG1. Type IV NRG1 upregulation by neuronal activity requires a CRE cis-element in the 5' UTR that binds CREB transcription factor. Each NRG1 isoform (Types I-VI) shows a distinct developmental expression pattern and is regulated by distinct mechanisms. RT-PCR for isoform quantification, CREB binding site mutation, luciferase reporter assays, neuronal activity manipulation (KCl depolarization) The Journal of neuroscience Medium 21653853
2013 RET and NRG1 genetically interact in Hirschsprung disease; in mouse neural crest cells, NRG1 inhibits GDNF-induced neuronal differentiation and GDNF negatively regulates NRG1 signaling by downregulating ErbB2 receptor expression, indicating that the balance between NRG1/ErbB and RET/GDNF signaling is critical for enteric nervous system neurogenesis/gliogenesis. Mouse neural crest cell culture, NRG1 and GDNF treatment, neuronal differentiation assays, receptor expression analysis by Western blot, conditional logistic regression for genetic interactions Human genetics Medium 23400839
2014 p63 transcription factor directly activates NRG1 gene transcription in mammary basal cells during pregnancy; basal cell NRG1 signals paracrinally to luminal cells via ERBB4, leading to STAT5A activation and luminal progenitor cell maturation for lactation. Genetic deletion of p63 exclusively in basal cells causes lactation failure due to failure of luminal cell proliferation and differentiation. Conditional p63 knockout in adult mammary basal cells, ChIP for p63 binding to Nrg1 promoter, ERBB4/STAT5A phosphorylation assays, mammary gland histology and functional lactation assay Developmental cell High 24412575
2014 TrkB interacts with ErbB4 (the NRG1 receptor) and this interaction is increased following NRG1 treatment; NRG1 induces GABAR-mediated TrkB activation and BDNF release via ErbB4, which in turn phosphorylates NMDA receptor subunit NR2B. TrkB kinase inhibition or TrkB siRNA suppresses NRG1-induced NR2B activation, and TrkB-ErbB4 interaction is reduced in prefrontal cortex of schizophrenia subjects. Co-immunoprecipitation, proximity ligation assay, TrkB inhibitor K252a, TrkB siRNA, TrkB knockout neurons, BDNF neutralizing antibody, TrkB domain mutants Cell communication and signaling Medium 25052836
2014 mTORC2 is a necessary component of HRG (NRG1)/ErbB2-induced cellular transformation; HRG activates PI3-kinase and mTORC1, and mTORC2 regulates the AKT/TSC2/mTORC1 axis by controlling AKT phosphorylation at both T308 (PDK1-dependent) and S473 (mTORC2-dependent) sites. Elimination of Rictor (mTORC2 component) abolishes both mTORC1 activation and HRG-mediated anchorage-independent growth. mTOR inhibitors (rapamycin and INK-128), Rictor siRNA/knockout, AKT phosphorylation assays at multiple sites, anchorage-independent growth assays Molecular cancer research Medium 24615340
2015 DISC1 inhibits NRG1-induced ErbB4 activation in mature cortical interneurons; this inhibition is mediated by competitive inhibition of ErbB4 binding to PSD95 by DISC1. Cell-type-specific gene modulation shows that interneuronal DISC1 affects NRG1-ErbB4-mediated phenotypes in fast-spiking interneuron-pyramidal neuron circuits. Cell-type-specific viral gene modulation in vitro and in vivo, mutant DISC1 mouse model, ErbB4 phosphorylation assays, PSD95-ErbB4 co-immunoprecipitation, electrophysiology Nature communications High 26656849
2015 NRG1 and HGF provide resistance to MEK inhibitor (trametinib) treatment in metastatic uveal melanoma; mechanistically, trametinib enhances NRG1 responsiveness, and NRG1 sustains AKT signaling through ERBB3 to bypass MEK inhibition. Inhibition of ERBB3 or AKT overcomes NRG1-provided resistance; stromal fibroblasts producing NRG1 confer resistance via paracrine signaling. Growth factor screening, NRG1 stimulation with MEK inhibitor, AKT/ERBB3 phosphorylation assays, ERBB3 inhibition, conditioned medium experiments, xenograft models Cancer research Medium 25952648
2016 CD74-NRG1 fusion gene expression promotes phosphorylation of ErbB2/3, activates PI3K/AKT/NF-κB signaling, and enhances expression of secreted IGF2 in an NF-κB-dependent manner; IGF2 activates IGF1R to create an autocrine/paracrine circuit that promotes cancer stem cell properties and tumor initiation. Inhibition of ErbB2, PI3K, NF-κB, or IGF2 suppresses tumor sphere formation. ErbB2/3 phosphorylation assays, NF-κB reporter, IGF2 ELISA, IGF1R phosphorylation, limiting dilution xenograft assay, pharmacological inhibition of pathway components Cancer research Medium 26837769
2016 A RET-ER81-NRG1 signaling pathway in mechanosensory neurons is required for Pacinian corpuscle formation; Ret maintains Er81 expression, Er81 (but not myelination-related NRG1 isoforms) controls specific Nrg1 isoform expression needed for axon-nonmyelinating Schwann cell communication. Ablating Nrg1 in mechanosensory neurons eliminates Pacinian corpuscles, and distinct NRG1 isoforms are used to interact with myelinating vs. non-myelinating Schwann cells. Er81 conditional knockout, Nrg1 conditional knockout in sensory neurons, histological analysis of Pacinian corpuscles, isoform-specific RT-PCR The Journal of neuroscience Medium 27707970
2017 Spironolactone inhibits ErbB4 receptor phosphorylation and acts as an antagonist of NRG1-ErbB4 signaling; transgenic mice overexpressing Nrg1 type III display cortical ErbB4 hyperphosphorylation, and spironolactone treatment reverses this hyperphosphorylation. Spironolactone treatment ameliorates schizophrenia-relevant behavioral endophenotypes (sensorimotor gating, hyperactivity, working memory) in Nrg1 type III transgenic mice and increases spontaneous inhibitory postsynaptic currents in cortical slices. Cell-based split-TEV assay screening, ErbB4 phosphorylation biochemical assays, NRG1 type III transgenic mice, behavioral tests, cortical slice electrophysiology EMBO molecular medicine Medium 28743784
2018 NRG1-Fc (a fusion protein of NRG1 EGF-like domain with IgG1 Fc domain) 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 secretagogue for FGF21 (largely dispensable for its metabolic effects) and directly targets hypothalamic POMC neurons to promote membrane depolarization and increase firing rate, establishing dual hepatic and central mechanisms. NRG1-Fc injection in obese mice, AKT phosphorylation in liver, electrophysiology of POMC neurons, FGF21 knockout mice, glucose tolerance tests JCI insight Medium 29515030
2018 SLC3A2-NRG1 fusion protein contains the SLC3A2 transmembrane domain and NRG1 EGF-like domain; it binds ERBB3 and ERBB4, promotes ERBB2-ERBB3 heterocomplex formation, and activates PI3K-AKT and MAPK signaling to drive colony formation and tumor growth. Dual inhibition of both ERBB2 and ERBB3 (but not either alone) is required to effectively block downstream signaling from this fusion. Ligand-receptor binding assays, ERBB2/3 co-immunoprecipitation, siRNA knockdown of ERBB2/ERBB3, pharmacological inhibition (pertuzumab, lumretuzumab, afatinib), xenograft models Molecular cancer therapeutics High 29959202
2019 NRG1 fusions (including CD74-NRG1, ATP1B1-NRG1, SDC4-NRG1) encode chimeric ligands that activate ERBB receptor tyrosine kinase family signaling by presenting the NRG1 EGF-like domain on the cell surface, leading to HER3-HER2 heterodimerization and downstream PI3K-AKT and MAPK pathway activation, driving oncogenic growth in solid tumors. RNA sequencing for fusion detection, ERBB2/3 phosphorylation assays in fusion-positive cell lines, xenograft tumor models, bispecific antibody (zenocutuzumab) blocking of HER3-NRG1 interaction Cancer discovery High 35135829
2020 NRG1 ubiquitination is increased in stress-susceptible mice; the E3 ubiquitin ligase Nedd4l directly targets NRG1 for ubiquitin-mediated degradation in the medial prefrontal cortex (mPFC). Overexpression of Nedd4l decreases NRG1 protein levels and causes vulnerability to stress-induced depression-like behaviors, while downregulation of Nedd4l in mPFC rescues stress vulnerability. NRG1 overexpression attenuates depression-like behaviors in CSDS model. Ubiquitination assays, Nedd4l overexpression/knockdown via viral vectors, NRG1 protein quantification, CSDS behavioral model, RNA sequencing Translational psychiatry Medium 32703967
2020 NRG1/ERBB4 autocrine signaling in cardiac endothelial cells (ECs) plays a role in modulating hypertrophic and fibrotic responses during early cardiac remodeling; EC-specific ERBB4 knockout attenuates myocardial hypertrophy and fibrosis 8 weeks after transverse aortic constriction and reduces fibrosis after angiotensin II treatment, though these differences normalize over time. RNA sequencing shows NRG1 controls expression of hypertrophic and fibrotic pathway genes in ECs. EC-specific Erbb4 conditional knockout, transverse aortic constriction model, angiotensin II treatment, cardiac histology, RNA sequencing of cultured ECs American journal of physiology. Heart and circulatory physiology Medium 32618511
2021 Biallelic variants in ERBB3 and ERBB2 (NRG1 receptors) cause a developmental disorder with HSCR, CIPO, peripheral neuropathy, and arthrogryposis; gut histology reveals aganglionosis and smooth muscle abnormalities. Mouse single-cell RNA sequencing and conditional ErbB3-deficient mouse show a primary role for ERBB3 in enteric progenitors. Functional analyses reveal the identified variants cause decreased expression or altered phosphorylation of the mutant receptors. Trio-exome sequencing, ErbB3 conditional mouse knockout, single-cell RNA sequencing, RT-qPCR and immunoblot of patient-derived fibroblasts and transfected cells The Journal of clinical investigation High 33497358
2021 VAMP2-NRG1 and SLC3A2-NRG1 fusion proteins are membrane-bound and display the NRG1 EGF-like domain extracellularly; KRAS mutation increases ADAM17 metalloprotease activity, which cleaves/sheds NRG1 from the SLC3A2-NRG1 fusion protein via KRAS-MEK-ERK signaling, enhancing ERBB2-ERBB3 phosphorylation and downstream PI3K/AKT/mTOR signaling even under oncogenic KRAS. MEK1/2 and ADAM17 inhibitors synergistically induce apoptosis. ADAM17 activity assays, MEK inhibitors, NRG1 shedding measurement, ERBB2/3 phosphorylation, xenograft and lung orthotopic tumor models Oncogene Medium 34743207
2021 Stromal cancer-associated fibroblasts (CAFs) express NRG1 and signal paracrinally to luminal breast cancer cells to phosphorylate HER3 (ERBB3) and activate AKT and ERK1/2; simultaneously, NRG1 drives a HER3-independent pro-fibrotic and migratory phenotype in CAFs themselves. HAS2 (Hyaluronan Synthase 2) is identified as a targetable molecule strongly correlated with NRG1 in CAFs. CAF-conditioned medium, NRG1 neutralizing antibodies, siRNA knockdown, HER3 phosphorylation assays, CAF migration/invasion assays, transcriptomic profiling Oncogene Medium 33692466
2021 NRG1/ErbB signaling controls dialogue between foxd3-positive neural crest-derived cells (NCdC) and macrophages during zebrafish fin regeneration; NCdC regulate macrophage recruitment and polarization through the NRG1/ErbB pathway, which is required for blastema formation. Chemical inhibition and transcriptomic analysis establish NRG1/ErbB pathway as the molecular link between NCdC and macrophage behavior during regeneration. Triple transgenic zebrafish live imaging, genetic NCdC depletion, NRG1/ErbB chemical inhibition, single-cell RNA sequencing, transcriptomic analysis Nature communications Medium 34732706
2021 NFKB2 directly binds the promoter region of NRG1 and inhibits NRG1 transcription; in IL-1β-stimulated nucleus pulposus cells, NFKB2 is upregulated leading to NRG1 downregulation. NRG1 activates ErbB2/3 to sustain PI3K-AKT signaling protecting against degenerative changes; NFKB2 silencing attenuates degeneration via NRG1, and this effect is reversed by NRG1 silencing. ChIP for NFKB2 binding to NRG1 promoter, luciferase reporter assays, siRNA knockdown, ErbB2/3 and AKT phosphorylation assays, cell viability and apoptosis assays Mechanisms of ageing and development Medium 34023356
2023 Nrg1 regulates cardiomyocyte-oriented cell division and trabeculae formation through endocardial Nrg1-to-myocardial ErbB2 signaling and phospho-ERK activation; early loss of Nrg1 reduces cardiomyocyte Pard3 and Crumbs2 polarity proteins, alters cytoskeletal actin gene expression, and shifts cardiomyocyte division orientation. Nrg1 is required for an EMT-like process in cardiomyocytes including migration, adhesion, and G2/M cell cycle progression. Ectopic Nrg1 overexpression causes S-phase arrest and prolonged trabeculation. Yap1 nuclear-cytoplasmic distribution is influenced by Nrg1 via pERK. Cardiac-specific Nrg1 knockout and overexpression, confocal imaging, transcriptomics, pERK and Pard3/Crumbs2 protein analysis, cell division orientation measurement, Yap1 nuclear-cytoplasmic localization imaging Circulation research High 37846569
2023 In pancreatic ductal adenocarcinoma, cancer-associated fibroblasts (CAFs) secrete NRG1 which activates ERBB2 and ERBB3 on cancer cells as a KRAS*-independent survival mechanism. Genetic extinction or pharmacological inhibition of KRAS* upregulates ERBB2 and ERBB3 expression in cancer cells, prompting utilization of CAF-derived NRG1. Genetic depletion or pharmacological inhibition of ERBB2/3 or NRG1 abolishes KRAS bypass and synergizes with KRASG12D inhibitors. KRAS* conditional extinction, NRG1 genetic depletion in CAFs, ERBB2/3 pharmacological inhibition, KRASG12D inhibitor combination in mouse and human PDAC models Genes & development High 37775182
2023 NRG1 fusions activate downstream signaling not only through HER2-HER3 heterodimers but also through HER4 independently of other HER family members, and through EGFR-HER3 signaling. Inhibition of HER4 and EGFR in addition to HER2/HER3 is necessary to effectively inhibit NRG1 fusion-driven tumor cell growth; pan-HER inhibition is more effective than selective targeting of HER2-HER3 or HER3 alone. Ba/F3 engineered cell lines with defined HER family member combinations, ERBB phosphorylation assays, cetuximab/trastuzumab/pertuzumab combination studies, in vitro and in vivo tumor growth assays with pan-HER TKIs Journal of thoracic oncology Medium 37678511
2024 Adipocyte precursors secrete NRG1 which activates ERBB3 (HER3) signaling on urothelial and lung cancer cells in a paracrine manner, conferring resistance to FGFR inhibition (erdafitinib). NRG1 expression is significantly higher in adipocyte precursors than terminally differentiated adipocytes. NRG1 knockdown in adipocyte precursors abrogates resistance; pharmacological inhibition of the NRG1/HER3 axis with pertuzumab reverses erdafitinib resistance in vivo. Co-culture of adipocyte precursors and cancer cells, NRG1 knockdown in adipocyte precursors, ERBB3 phosphorylation assays, pertuzumab treatment, xenograft survival experiments, scRNA-seq Cancer research Medium 38175774

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2002 Neuregulin 1 and susceptibility to schizophrenia. American journal of human genetics 1264 12145742
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1992 Identification of heregulin, a specific activator of p185erbB2. Science (New York, N.Y.) 992 1350381
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2008 Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature genetics 817 18583979
2009 Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 805 19632177
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
1993 Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 713 8096067
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. The EMBO journal 561 8617201
1994 Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. The Journal of biological chemistry 554 7514177
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
1992 Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell 530 1348215
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2006 Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nature medicine 448 16767099
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1998 Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. The Journal of biological chemistry 425 9553078
2002 Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. American journal of human genetics 415 12478479
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2007 Notch signaling is essential for ventricular chamber development. Developmental cell 403 17336907
1995 Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. The EMBO journal 357 7556068
2006 Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biological psychiatry 341 16442083
1997 Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 340 9168115
2009 Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Archives of general psychiatry 335 19736351
1997 Isoform-specific expression and function of neuregulin. Development (Cambridge, England) 330 9342050
2006 Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease. Proceedings of the National Academy of Sciences of the United States of America 323 16618933
1996 GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron 321 8780647
2003 Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 308 12646923
2004 Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nature neuroscience 305 15162166
1997 Role of GGF/neuregulin signaling in interactions between migrating neurons and radial glia in the developing cerebral cortex. Development (Cambridge, England) 286 9342043
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 216 31311833
2010 Nrg1/ErbB signaling networks in Schwann cell development and myelination. Seminars in cell & developmental biology 204 20832498
2019 Diverse NLR immune receptors activate defence via the RPW8-NLR NRG1. The New phytologist 188 30582759
2019 Detection of NRG1 Gene Fusions in Solid Tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 180 30988082
2006 Association of the NRG1 gene and schizophrenia: a meta-analysis. Molecular psychiatry 173 16520822
2022 Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements. Cancer discovery 140 35135829
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 135 21653853
2021 Pathogen effector recognition-dependent association of NRG1 with EDS1 and SAG101 in TNL receptor immunity. Nature communications 133 34099661
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
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 124 32916265
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
2014 Basal cell signaling by p63 controls luminal progenitor function and lactation via NRG1. Developmental cell 95 24412575
2005 AlphaVbeta3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer. Oncogene 87 15782133
2005 Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich glycoprotein (HRG). Journal of thrombosis and haemostasis : JTH 79 15869579
1995 ErbB-3 mediates differential mitogenic effects of NDF/heregulin isoforms on mouse keratinocytes. Oncogene 77 7731691
2014 Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 75 25501131
2025 Efficacy of Zenocutuzumab in NRG1 Fusion-Positive Cancer. The New England journal of medicine 73 39908431
2012 BRG1 and NRG1 form a novel feedback circuit regulating Candida albicans hypha formation and virulence. Molecular microbiology 73 22757963
2009 NRG1 / ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. Pigment cell & melanoma research 70 19659570
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 63 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 60 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
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
2015 Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma. Cancer research 57 25952648
2022 HRG-9 homologues regulate haem trafficking from haem-enriched compartments. Nature 55 36261532
2010 LH-induced neuregulin 1 (NRG1) type III transcripts control granulosa cell differentiation and oocyte maturation. Molecular endocrinology (Baltimore, Md.) 54 21047912
2019 Mechanisms of the Multitasking Endothelial Protein NRG-1 as a Compensatory Factor During Chronic Heart Failure. Circulation. Heart failure 52 31607147
1999 Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts as mediator of progestins proliferative effects in mouse mammary adenocarcinomas. Oncogene 49 10597237
2020 Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series. The oncologist 47 32852072
1998 Chronically denervated rat Schwann cells respond to GGF in vitro. Glia 47 9775980
2007 The role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland. Schizophrenia research 46 17300918
1999 Characteristics of EGFR family-mediated HRG signals in human ovarian cancer. Journal of cellular biochemistry 45 10733345
2013 Discovery, validation and characterization of Erbb4 and Nrg1 haplotypes using data from three genome-wide association studies of schizophrenia. PloS one 42 23301017
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) 38 38348690
1999 Differential binding of histidine-rich glycoprotein (HRG) to human IgG subclasses and IgG molecules containing kappa and lambda light chains. The Journal of biological chemistry 38 10514432
2018 NRG1-Fc improves metabolic health via dual hepatic and central action. JCI insight 37 29515030
2014 Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease. Journal of pediatric surgery 37 25475805
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 35 28573357
2017 Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice. EMBO molecular medicine 35 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 34 26134228
2023 Nrg1 Regulates Cardiomyocyte Migration and Cell Cycle in Ventricular Development. Circulation research 33 37846569
2020 The role of endothelial autocrine NRG1/ERBB4 signaling in cardiac remodeling. American journal of physiology. Heart and circulatory physiology 33 32618511
2018 Dual Targeting of ERBB2/ERBB3 for the Treatment of SLC3A2-NRG1-Mediated Lung Cancer. Molecular cancer therapeutics 32 29959202
2021 Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans. The Journal of clinical investigation 31 33497358
2020 CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer's disease. Alzheimer's research & therapy 31 32690068
2009 DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study. Neuropsychobiology 31 19439994
2018 Astraglaus polysaccharide protects diabetic cardiomyopathy by activating NRG1/ErbB pathway. Bioscience trends 30 29607874
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
2008 Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population. Journal of human genetics 29 18704261
2023 Effector XopQ-induced stromule formation in Nicotiana benthamiana depends on ETI signaling components ADR1 and NRG1. Plant physiology 28 36259930
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
2013 HRG-1 enhances cancer cell invasive potential and couples glucose metabolism to cytosolic/extracellular pH gradient regulation by the vacuolar-H(+) ATPase. Oncogene 28 24141772
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 27 35876932
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
2017 The acceleration of reproductive aging in Nrg1flox/flox ;Cyp19-Cre female mice. Aging cell 26 28857490
2016 HRG/HER2/HER3 signaling promotes AhR-mediated Memo-1 expression and migration in colorectal cancer. Oncogene 26 27941874
2017 Inter-organ signalling by HRG-7 promotes systemic haem homeostasis. Nature cell biology 25 28581477
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
2021 Effects of Age, Diet CP, NDF, EE, and Starch on the Rumen Bacteria Community and Function in Dairy Cattle. Microorganisms 23 34442867
1995 Heregulin (HRG)-induced mitogenic signaling and cytotoxic activity of a HRG/PE40 ligand toxin in human breast cancer cells. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 23 9019162
2013 HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment. Angiogenesis 22 23793459
1998 HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency. Blood 22 9414276
2023 Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer. Genes & development 21 37775182
2021 NRG1/ErbB signalling controls the dialogue between macrophages and neural crest-derived cells during zebrafish fin regeneration. Nature communications 21 34732706
2021 Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1. Oncogene 21 34743207
2020 HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma. Theranostics 21 32929358
2019 lncRNA CASC9 regulates cell migration and invasion in hemangioma endothelial cells by targeting miR-125a-3p/Nrg1. OncoTargets and therapy 21 30662268
2021 Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts. Oncogene 20 33692466
2020 Nedd4l downregulation of NRG1 in the mPFC induces depression-like behaviour in CSDS mice. Translational psychiatry 20 32703967
2009 Regulation of histidine-rich glycoprotein (HRG) function via plasmin-mediated proteolytic cleavage. The Biochemical journal 20 19712047
1998 Predicting forage indigestible NDF from lignin concentration. Journal of animal science 20 9621956
2020 Ranolazine protects against diabetic cardiomyopathy by activating the NOTCH1/NRG1 pathway. Life sciences 19 32828943
2014 Identification of mTORC2 as a necessary component of HRG/ErbB2-dependent cellular transformation. Molecular cancer research : MCR 19 24615340
2014 TrkB interacts with ErbB4 and regulates NRG1-induced NR2B phosphorylation in cortical neurons before synaptogenesis. Cell communication and signaling : CCS 18 25052836
2000 Histidine-rich glycoprotein (HRG) Tokushima 2: novel HRG deficiency, molecular and cellular characterization. Thrombosis and haemostasis 18 11057869
2019 MCLA-128 Fights NRG1 Fusion-Positive Cancers. Cancer discovery 17 31685488
2012 Regulation of HRG-β1-induced proliferation, migration and invasion of MCF-7 cells by upregulation of GPR30 expression. Molecular medicine reports 17 22576740
2011 Expression of NRG1 and its receptors in human bladder cancer. British journal of cancer 17 21364580
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
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 16 33541789
2012 Aberrant high expression of NRG1 gene in Hirschsprung disease. Journal of pediatric surgery 16 22974608
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 15 37678511
2021 NFKB2 inhibits NRG1 transcription to affect nucleus pulposus cell degeneration and inflammation in intervertebral disc degeneration. Mechanisms of ageing and development 15 34023356
2015 Polymorphisms of dopamine pathway genes NRG1 and LMX1A are associated with cognitive performance in bipolar disorder. Bipolar disorders 15 26534905
2024 Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma. Cancer research 14 38175774