The neuregulins, including NRG4, activate type-1 growth factor receptors (see EGFR; MIM 131550) to initiating cell-to-cell signaling through tyrosine phosphorylation (Harari et al., 1999 [PubMed 10348342]).[supplied by OMIM, Mar 2008] See more...

Aliases for NRG4 Gene

Aliases for NRG4 Gene

  • Neuregulin 4 2 3 5
  • Pro-Neuregulin-4, Membrane-Bound Isoform 3 4
  • Pro-NRG4 3 4
  • HRG4 2 3
  • Heregulin 4 3
  • NRG4 5

External Ids for NRG4 Gene

Previous GeneCards Identifiers for NRG4 Gene

  • GC15M074022
  • GC15M076233
  • GC15M052990

Summaries for NRG4 Gene

Entrez Gene Summary for NRG4 Gene

  • The neuregulins, including NRG4, activate type-1 growth factor receptors (see EGFR; MIM 131550) to initiating cell-to-cell signaling through tyrosine phosphorylation (Harari et al., 1999 [PubMed 10348342]).[supplied by OMIM, Mar 2008]

GeneCards Summary for NRG4 Gene

NRG4 (Neuregulin 4) is a Protein Coding gene. Diseases associated with NRG4 include Type 2 Diabetes Mellitus. Among its related pathways are RET signaling and Agrin Interactions at Neuromuscular Junction. Gene Ontology (GO) annotations related to this gene include signaling receptor binding and growth factor activity. An important paralog of this gene is NRG3.

UniProtKB/Swiss-Prot Summary for NRG4 Gene

  • Low affinity ligand for the ERBB4 tyrosine kinase receptor. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. Does not bind to the ERBB1, ERBB2 and ERBB3 receptors (By similarity).

Gene Wiki entry for NRG4 Gene

No data available for CIViC Summary , Tocris Summary , PharmGKB "VIP" Summary , Rfam classification and piRNA Summary for NRG4 Gene

Genomics for NRG4 Gene

GeneHancer (GH) Regulatory Elements Pubs

Promoters and enhancers for NRG4 Gene
GeneHancer (GH) Identifier GH Type GH
Score
GH Sources Gene Association Score Total Score TSS distance (kb) Number of Genes Away Size (kb) Transcription Factor
Binding Sites
Gene Targets
GH15J076011 Promoter/Enhancer 1.6 EPDnew Ensembl ENCODE CraniofacialAtlas 250.2 +58.0 58035 2.4 NCOR1 BHLHE40 MNT MAX ARNT NBN RXRA RFX5 ZNF316 TBP lnc-NRG4-1 NRG4 FBXO22 MIR631 MAN2C1 RF00015-020 TMEM266
GH15J076069 Enhancer 0.3 Ensembl 250.7 -1.8 -1771 2.8 TOE1 NRG4 TMEM266 MIR631 SCAPER MAN2C1 piR-57133-193 lnc-FBXO22-5 ETFA
GH15J076058 Promoter/Enhancer 1.9 EPDnew Ensembl ENCODE CraniofacialAtlas 21.2 +10.0 10030 2.4 ZNF654 ZNF600 POLR2A ZIC2 ZBTB10 FEZF1 ZNF341 CTCF SIN3A ZNF585B TMEM266 lnc-FBXO22-5 NRG4 FBXO22 ENSG00000187812 DNM1P35 lnc-ETFA-2
GH15J075901 Promoter/Enhancer 2.1 EPDnew Ensembl ENCODE CraniofacialAtlas 18.3 +166.4 166412 4.4 BCLAF1 SP1 ZNF207 NCOR1 MYC IKZF1 ZNF600 SIX5 ZNF580 ZMYM3 FBXO22 DNM1P35 SIN3A NRG4 SNUPN MAN2C1 ENSG00000260274 UBE2Q2 HSALNG0107327 RN7SL510P
GH15J076057 Promoter/Enhancer 1 Ensembl ENCODE 21.3 +12.3 12333 0.6 CTCF REST TRIM22 PRDM1 RAD21 IRF4 RFX5 SMC3 SMARCA5 BHLHE40 lnc-ETFA-2 NRG4 MIR631 TMEM266 FBXO22
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around NRG4 on the GeneHancer Hub at the UCSC Golden Path

Cistromic (ChIP-Seq) regulation report from SPP (The Signaling Pathways Project) for NRG4

Top Transcription factor binding sites by QIAGEN in the NRG4 gene promoter:
  • AML1a
  • CUTL1
  • E4BP4
  • FOXJ2
  • FOXJ2 (long isoform)
  • HFH-1
  • Hlf
  • IRF-1
  • Pax-4a
  • TGIF

Genomic Locations for NRG4 Gene

Latest Assembly
chr15:75,933,219-76,069,830
(GRCh38/hg38)
Size:
136,612 bases
Orientation:
Minus strand

Previous Assembly
chr15:76,233,277-76,304,765
(GRCh37/hg19 by Entrez Gene)
Size:
71,489 bases
Orientation:
Minus strand

chr15:76,228,310-76,352,136
(GRCh37/hg19 by Ensembl)
Size:
123,827 bases
Orientation:
Minus strand

Genomic View for NRG4 Gene

Genes around NRG4 on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
NRG4 Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for NRG4 Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for NRG4 Gene

Proteins for NRG4 Gene

  • Protein details for NRG4 Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    Q8WWG1-NRG4_HUMAN
    Recommended name:
    Pro-neuregulin-4, membrane-bound isoform
    Protein Accession:
    Q8WWG1
    Secondary Accessions:
    • A6NIE8

    Protein attributes for NRG4 Gene

    Size:
    115 amino acids
    Molecular mass:
    12722 Da
    Quaternary structure:
    • Interacts with ERBB4.

neXtProt entry for NRG4 Gene

Post-translational modifications for NRG4 Gene

  • Proteolytic cleavage close to the plasma membrane on the external face leads to the release of the soluble growth factor form.
  • Extensive glycosylation precedes the proteolytic cleavage.
  • Glycosylation at Asn39

Antibodies for research

  • Abcam antibodies for NRG4
  • Boster Bio Antibodies for NRG4

Protein products for research

  • Abcam proteins for NRG4

No data available for DME Specific Peptides for NRG4 Gene

Domains & Families for NRG4 Gene

Gene Families for NRG4 Gene

HGNC:
Human Protein Atlas (HPA):
  • Predicted membrane proteins
  • Predicted secreted proteins

Protein Domains for NRG4 Gene

InterPro:
Blocks:
  • Type I EGF

Suggested Antigen Peptide Sequences for NRG4 Gene

GenScript: Design optimal peptide antigens:
  • Pro-neuregulin-4, membrane-bound isoform (NRG4_HUMAN)
  • Neuregulin 4 (Q0P6N4_HUMAN)
  • Neuregulin 4 (Q0P6N5_HUMAN)

Graphical View of Domain Structure for InterPro Entry

Q8WWG1

UniProtKB/Swiss-Prot:

NRG4_HUMAN :
  • The cytoplasmic domain may be involved in the regulation of trafficking and proteolytic processing. Regulation of the proteolytic processing involves initial intracellular domain dimerization (By similarity).
  • Belongs to the neuregulin family.
Domain:
  • The cytoplasmic domain may be involved in the regulation of trafficking and proteolytic processing. Regulation of the proteolytic processing involves initial intracellular domain dimerization (By similarity).
  • ERBB receptor binding is elicited entirely by the EGF-like domain.
Family:
  • Belongs to the neuregulin family.
genes like me logo Genes that share domains with NRG4: view

Function for NRG4 Gene

Molecular function for NRG4 Gene

UniProtKB/Swiss-Prot Function:
Low affinity ligand for the ERBB4 tyrosine kinase receptor. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. Does not bind to the ERBB1, ERBB2 and ERBB3 receptors (By similarity).

Phenotypes From GWAS Catalog for NRG4 Gene

Gene Ontology (GO) - Molecular Function for NRG4 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005102 signaling receptor binding IEA --
GO:0005515 protein binding IPI 21516116
GO:0008083 growth factor activity IEA --
genes like me logo Genes that share ontologies with NRG4: view

Phenotypes for NRG4 Gene

genes like me logo Genes that share phenotypes with NRG4: view

Animal Models for research

  • Taconic Biosciences Mouse Models for NRG4

Inhibitory RNAs for research

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for NRG4

No data available for Enzyme Numbers (IUBMB) , Human Phenotype Ontology , Animal Models , Transcription Factor Targets and HOMER Transcription for NRG4 Gene

Localization for NRG4 Gene

Subcellular locations from UniProtKB/Swiss-Prot for NRG4 Gene

[Pro-neuregulin-4, membrane-bound isoform]: Cell membrane. Single-pass type I membrane protein. Note=Does not seem to be active. {ECO:0000250}.
[Neuregulin-4]: Secreted.

Subcellular locations from

COMPARTMENTS
Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for NRG4 gene
Compartment Confidence
plasma membrane 4
extracellular 4
mitochondrion 2
cytoskeleton 1
nucleus 1
endoplasmic reticulum 1
cytosol 1

Gene Ontology (GO) - Cellular Components for NRG4 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005576 extracellular region TAS --
GO:0005886 plasma membrane IEA --
GO:0016020 membrane IEA --
GO:0016021 integral component of membrane IEA --
genes like me logo Genes that share ontologies with NRG4: view

No data available for Subcellular locations from the Human Protein Atlas (HPA) for NRG4 Gene

Pathways & Interactions for NRG4 Gene

PathCards logo

SuperPathways for NRG4 Gene

SuperPathway Contained pathways
1 RET signaling
2 Apoptotic Pathways in Synovial Fibroblasts
.85
.85
.84
.84
.74
.72
.66
.65
.64
.62
.61
.60
.57
.57
3 Signaling by ERBB2
4 PI3K/AKT activation
5 GPCR Pathway
.73
.73
.62
.59
.58
.58
.55
genes like me logo Genes that share pathways with NRG4: view

Pathways by source for NRG4 Gene

1 GeneGo (Thomson Reuters) pathway for NRG4 Gene
  • Development ERBB-family signaling
58 Qiagen pathways for NRG4 Gene
  • 14-3-3 Induced Intracellular Signaling
  • Actin-Based Motility by Rho Family GTPases
  • Activation of cAMP-Dependent PKA
  • Activation of PKA through GPCR
  • Activation of PKC through GPCR

SIGNOR curated interactions for NRG4 Gene

Activates:

Gene Ontology (GO) - Biological Process for NRG4 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0000165 MAPK cascade TAS --
GO:0007399 nervous system development IEA --
GO:0038128 ERBB2 signaling pathway TAS --
GO:0051897 positive regulation of protein kinase B signaling TAS --
GO:2000145 regulation of cell motility TAS --
genes like me logo Genes that share ontologies with NRG4: view

Drugs & Compounds for NRG4 Gene

(1) Drugs for NRG4 Gene - From: Novoseek

Name Status Disease Links Group Role Mechanism of Action Clinical Trials
genes like me logo Genes that share compounds with NRG4: view

Transcripts for NRG4 Gene

mRNA/cDNA for NRG4 Gene

1 REFSEQ mRNAs :
9 NCBI additional mRNA sequence :
16 Ensembl transcripts including schematic representations, and UCSC links to gene/alias where relevant :

Inhibitory RNAs for research

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for NRG4

Alternative Splicing Database (ASD) splice patterns (SP) for NRG4 Gene

No ASD Table

Relevant External Links for NRG4 Gene

GeneLoc Exon Structure for
NRG4

Expression for NRG4 Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and SAGE for NRG4 Gene

mRNA differential expression in normal tissues according to GTEx for NRG4 Gene

This gene is overexpressed in Brain - Cerebellar Hemisphere (x6.2), Brain - Cerebellum (x5.3), and Pancreas (x4.2).

Transcriptomic regulation report from SPP (The Signaling Pathways Project) for NRG4

SOURCE GeneReport for Unigene cluster for NRG4 Gene:

Hs.732438

Evidence on tissue expression from TISSUES for NRG4 Gene

  • Liver(4.4)
  • Nervous system(3.2)
  • Pancreas(2.4)
  • Muscle(2.3)
genes like me logo Genes that share expression patterns with NRG4: view

Primer products for research

No data available for Protein differential expression in normal tissues , Protein expression , Protein tissue co-expression partners , mRNA Expression by UniProt/SwissProt and Phenotype-based relationships between genes and organs from Gene ORGANizer for NRG4 Gene

Orthologs for NRG4 Gene

This gene was present in the common ancestor of chordates.

Orthologs for NRG4 Gene

Organism Taxonomy Gene Similarity Type Details
Chimpanzee
(Pan troglodytes)
Mammalia NRG4 29 30
  • 98.84 (n)
OneToOne
Cow
(Bos Taurus)
Mammalia NRG4 29
  • 87.83 (n)
Rat
(Rattus norvegicus)
Mammalia Nrg4 29
  • 84.64 (n)
Mouse
(Mus musculus)
Mammalia Nrg4 29 16 30
  • 82.61 (n)
OneToOne
Dog
(Canis familiaris)
Mammalia NRG4 30
  • 77 (a)
OneToOne
Oppossum
(Monodelphis domestica)
Mammalia NRG4 30
  • 67 (a)
OneToOne
Platypus
(Ornithorhynchus anatinus)
Mammalia NRG4 30
  • 41 (a)
OneToOne
Chicken
(Gallus gallus)
Aves NRG4 29 30
  • 69.44 (n)
OneToOne
Species where no ortholog for NRG4 was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Eremothecium gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • African clawed frog (Xenopus laevis)
  • African malaria mosquito (Anopheles gambiae)
  • Alicante grape (Vitis vinifera)
  • Alpha proteobacteria (Wolbachia pipientis)
  • Amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • Baker's yeast (Saccharomyces cerevisiae)
  • Barley (Hordeum vulgare)
  • Beta proteobacteria (Neisseria meningitidis)
  • Bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • Common water flea (Daphnia pulex)
  • Corn (Zea mays)
  • E. coli (Escherichia coli)
  • Filamentous fungi (Aspergillus nidulans)
  • Firmicute Bacteria (Streptococcus pneumoniae)
  • Fission Yeast (Schizosaccharomyces pombe)
  • Fruit Fly (Drosophila melanogaster)
  • Green Algae (Chlamydomonas reinhardtii)
  • Honey Bee (Apis mellifera)
  • K. Lactis Yeast (Kluyveromyces lactis)
  • Lizard (Anolis carolinensis)
  • Loblloly Pine (Pinus taeda)
  • Malaria Parasite (Plasmodium falciparum)
  • Medicago Trunc (Medicago Truncatula)
  • Moss (Physcomitrella patens)
  • Orangutan (Pongo pygmaeus)
  • Pig (Sus scrofa)
  • Rainbow Trout (Oncorhynchus mykiss)
  • Rice (Oryza sativa)
  • Rice Blast Fungus (Magnaporthe grisea)
  • Schistosome Parasite (Schistosoma mansoni)
  • Sea Anemone (Nematostella vectensis)
  • Sea Vase (Ciona intestinalis)
  • Sea Squirt (Ciona savignyi)
  • Sea Urchin (Strongylocentrotus purpuratus)
  • Sorghum (Sorghum bicolor)
  • Soybean (Glycine max)
  • Stem Rust Fungus (Puccinia graminis)
  • Sugarcane (Saccharum officinarum)
  • Thale Cress (Arabidopsis thaliana)
  • Tomato (Lycopersicon esculentum)
  • Toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • Tropical Clawed Frog (Silurana tropicalis)
  • Wheat (Triticum aestivum)
  • Worm (Caenorhabditis elegans)
  • Zebrafish (Danio rerio)

Evolution for NRG4 Gene

ENSEMBL:
Gene Tree for NRG4 (if available)
TreeFam:
Gene Tree for NRG4 (if available)
Aminode:
Evolutionary constrained regions (ECRs) for NRG4: view image
Alliance of Genome Resources:
Additional Orthologs for NRG4

Paralogs for NRG4 Gene

Paralogs for NRG4 Gene

(9) SIMAP similar genes for NRG4 Gene using alignment to 7 proteins:

  • NRG4_HUMAN
  • E9PJI7_HUMAN
  • F8W729_HUMAN
  • H3BP63_HUMAN
  • Q0P6N4_HUMAN
  • Q0P6N5_HUMAN
  • Q0P6N6_HUMAN
genes like me logo Genes that share paralogs with NRG4: view

Variants for NRG4 Gene

Sequence variations, with clinical significance, from ClinVar and Humsavar, with links to dbSNP for NRG4 Gene

SNP ID Clinical significance and condition Chr 15 pos Variation AA Info Type
rs74024031 Benign: not provided 75,961,970(-) C/T
NM_138573.4(NRG4):c.109G>A (p.Val37Ile)
MISSENSE

dbSNP identifiers (rs#s) for variants without ClinVar clinical significance for NRG4 Gene

All consequence types are included: molecular consequences (e.g. missense, synonymous), and location-based (e.g. intron, upstream).

Structural Variations from Database of Genomic Variants (DGV) for NRG4 Gene

Variant ID Type Subtype PubMed ID
dgv2622n100 CNV gain 25217958
esv2749895 CNV deletion 23290073
esv2749898 CNV deletion 23290073
esv2749900 CNV deletion 23290073
esv3636933 CNV gain 21293372
nsv1108966 CNV deletion 24896259
nsv1116463 OTHER inversion 24896259
nsv518214 CNV loss 19592680
nsv518261 CNV loss 19592680
nsv569998 CNV gain 21841781

Variation tolerance for NRG4 Gene

Residual Variation Intolerance Score: 44.6% of all genes are more intolerant (likely to be disease-causing)
Gene Damage Index Score: 1.74; 33.04% of all genes are more intolerant (likely to be disease-causing)

Additional Variant Information for NRG4 Gene

Human Gene Mutation Database (HGMD)
NRG4
SNPedia medical, phenotypic, and genealogical associations of SNPs for
NRG4
Leiden Open Variation Database (LOVD)
NRG4

SNP Genotyping and Copy Number Assays for research

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot for NRG4 Gene

Disorders for NRG4 Gene

MalaCards: The human disease database

(1) MalaCards diseases for NRG4 Gene - From: COP and GCD

Disorder Aliases PubMed IDs
type 2 diabetes mellitus
  • t2d
- elite association - COSMIC cancer census association via MalaCards
Search NRG4 in MalaCards View complete list of genes associated with diseases

Additional Disease Information for NRG4

Human Genome Epidemiology Navigator
(HuGE)
Atlas
ATLAS of Genetics and Cytogenetics in Oncology and Haematology
Open Targets Platform
Open Targets Platform
genes like me logo Genes that share disorders with NRG4: view

No data available for UniProtKB/Swiss-Prot and Genatlas for NRG4 Gene

Publications for NRG4 Gene

  1. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. (PMID: 25401691) Wang GX … Lin JD (Nature medicine 2014) 2 3
  2. Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study. (PMID: 20628086) Bailey SD … DREAM investigators (Diabetes care 2010) 3 40
  3. Characterization of the cell membrane-associated products of the Neuregulin 4 gene. (PMID: 17684490) Hayes NV … Gullick WJ (Oncogene 2008) 3 22
  4. Identification and characterization of novel spliced variants of neuregulin 4 in prostate cancer. (PMID: 17545517) Hayes NV … Gullick WJ (Clinical cancer research : an official journal of the American Association for Cancer Research 2007) 3 22
  5. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. (PMID: 15583696) Memon AA … Nexo E (British journal of cancer 2004) 3 22

Products for NRG4 Gene

Sources for NRG4 Gene