Human Gene NRG4 (uc002bbo.3)
  Description: Homo sapiens neuregulin 4 (NRG4), mRNA.
RefSeq Summary (NM_138573): 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]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments.
Transcript (Including UTRs)
   Position: hg19 chr15:76,234,328-76,304,785 Size: 70,458 Total Exon Count: 6 Strand: -
Coding Region
   Position: hg19 chr15:76,235,979-76,303,571 Size: 67,593 Coding Exon Count: 5 

Page IndexSequence and LinksUniProtKB CommentsPrimersGenetic AssociationsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated at UCSC: 2013-06-14

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr15:76,234,328-76,304,785)mRNA (may differ from genome)Protein (115 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
AlphaFoldBioGPSEnsemblEntrez GeneExonPrimerGeneCards
GeneNetworkH-INVHGNCHPRDLynxMGI
neXtProtOMIMPubMedReactomeUniProtKBWikipedia
BioGrid CRISPR DB

-  Comments and Description Text from UniProtKB
  ID: NRG4_HUMAN
DESCRIPTION: RecName: Full=Pro-neuregulin-4, membrane-bound isoform; Short=Pro-NRG4; Contains: RecName: Full=Neuregulin-4; Short=NRG-4;
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).
SUBUNIT: Interacts with ERBB4 (By similarity).
SUBCELLULAR LOCATION: Pro-neuregulin-4, membrane-bound isoform: Cell membrane; Single-pass type I membrane protein (By similarity). Note=Does not seem to be active (By similarity).
SUBCELLULAR LOCATION: Neuregulin-4: Secreted (By similarity).
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).
DOMAIN: ERBB receptor binding is elicited entirely by the EGF-like domain (By similarity).
PTM: Proteolytic cleavage close to the plasma membrane on the external face leads to the release of the soluble growth factor form (By similarity).
PTM: Extensive glycosylation precedes the proteolytic cleavage (By similarity).
SIMILARITY: Belongs to the neuregulin family.
SIMILARITY: Contains 1 EGF-like domain.

-  Primer design for this transcript
 

Primer3Plus can design qPCR Primers that straddle exon-exon-junctions, which amplify only cDNA, not genomic DNA.
Click here to load the transcript sequence and exon structure into Primer3Plus

Exonprimer can design one pair of Sanger sequencing primers around every exon, located in non-genic sequence.
Click here to open Exonprimer with this transcript

To design primers for a non-coding sequence, zoom to a region of interest and select from the drop-down menu: View > In External Tools > Primer3


-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): NRG4
CDC HuGE Published Literature: NRG4

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene
  • D013749 Tetrachlorodibenzodioxin
  • C028474 1,4-bis(2-(3,5-dichloropyridyloxy))benzene
  • C029141 2,2,5,7,8-pentamethyl-1-hydroxychroman
  • D015085 2,4,5-Trichlorophenoxyacetic Acid
  • C028451 3,4,3',4'-tetrachlorobiphenyl
  • C009505 4,4'-diaminodiphenylmethane
  • D015123 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
  • D000082 Acetaminophen
  • D016604 Aflatoxin B1
  • D000393 Air Pollutants
          more ... click here to view the complete list

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 11.43 RPKM in Brain - Cerebellar Hemisphere
Total median expression: 81.51 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -33.90182-0.186 Picture PostScript Text
3' UTR -398.101651-0.241 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR000742 - EG-like_dom
IPR013032 - EGF-like_CS

Pfam Domains:
PF00008 - EGF-like domain

SCOP Domains:
57196 - EGF/Laminin

ModBase Predicted Comparative 3D Structure on Q8WWG1
FrontTopSide
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologNo orthologNo orthologNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
      
      
      

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0004713 protein tyrosine kinase activity
GO:0005088 Ras guanyl-nucleotide exchange factor activity
GO:0005102 receptor binding
GO:0005515 protein binding
GO:0008083 growth factor activity
GO:0046934 phosphatidylinositol-4,5-bisphosphate 3-kinase activity

Biological Process:
GO:0000165 MAPK cascade
GO:0010469 regulation of receptor activity
GO:0018108 peptidyl-tyrosine phosphorylation
GO:0035556 intracellular signal transduction
GO:0038128 ERBB2 signaling pathway
GO:0046854 phosphatidylinositol phosphorylation
GO:0048513 animal organ development
GO:0051897 positive regulation of protein kinase B signaling
GO:2000145 regulation of cell motility

Cellular Component:
GO:0005576 extracellular region
GO:0005615 extracellular space
GO:0005622 intracellular
GO:0005886 plasma membrane
GO:0016020 membrane
GO:0016021 integral component of membrane


-  Descriptions from all associated GenBank mRNAs
  CR749519 - Homo sapiens mRNA; cDNA DKFZp779N0541 (from clone DKFZp779N0541).
BX538100 - Homo sapiens mRNA; cDNA DKFZp779N1944 (from clone DKFZp779N1944); complete cds.
AK307362 - Homo sapiens cDNA, FLJ97310.
AK311204 - Homo sapiens cDNA, FLJ18246.
AK311507 - Homo sapiens cDNA, FLJ18549.
BC017568 - Homo sapiens neuregulin 4, mRNA (cDNA clone MGC:22713 IMAGE:4071605), complete cds.
HQ448724 - Synthetic construct Homo sapiens clone IMAGE:100072169; CCSB007557_01 neuregulin 4 (NRG4) gene, encodes complete protein.
KJ895587 - Synthetic construct Homo sapiens clone ccsbBroadEn_04981 NRG4 gene, encodes complete protein.
AM392364 - Homo sapiens mRNA for neuregulin 4 isoform A2 (NRG4 gene).
AM392365 - Homo sapiens mRNA for neuregulin 4 isoform B2 (NRG4 gene).
JD566812 - Sequence 547836 from Patent EP1572962.
JD079273 - Sequence 60297 from Patent EP1572962.
AM392366 - Homo sapiens mRNA for neuregulin 4 isoform B3 (NRG4 gene).

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04012 - ErbB signaling pathway

Reactome (by CSHL, EBI, and GO)

Protein Q8WWG1 (Reactome details) participates in the following event(s):

R-HSA-1236398 ERBB4 binds NRGs or EGF-like ligands
R-HSA-1963589 ERBB2 forms heterodimers with ligand-activated ERBB receptors: EGFR, ERBB3 and ERBB4
R-NUL-1251988 Cleavage of P-ERBB4jmA isoforms by Adam17
R-HSA-1250220 Homodimerization of ERBB4
R-HSA-1977958 ERBB4 forms heterodimers with ERBB3
R-HSA-1977959 ERBB4 forms heterodimers with EGFR
R-HSA-1250346 Binding of PI3K to p-ERBB2:p-ERBB4 CYT-1 heterodimers
R-HSA-1250357 SHC1 binds P-ERBB4 isoform dimers
R-HSA-1250315 Trans-autophosphorylation of ERBB4 homodimers
R-HSA-1251992 Cleavage of P-ERBB4jmA isoforms by ADAM17
R-HSA-1250353 Binding of p85 subunit of PI3K (PIK3R1) to p-ERBB4cyt1 homodimers
R-HSA-1963582 Trans-autophosphorylation of ERBB2 heterodimers
R-HSA-1963586 SRC family kinases phosphorylate ERBB2
R-HSA-1963581 Trans-autophosphorylation of p-Y877-ERBB2 heterodimers
R-HSA-1306969 GRB2:SOS1 complex binds phosphorylated ERBB4:ERBB2 heterodimers
R-HSA-1250380 Recruitment of GRB2:SOS1 to phosphorylated SHC1 in complex with phosphorylated ERBB4 homodimers
R-HSA-1250348 Phosphorylation of SHC1 by ERBB4 homodimers
R-HSA-1250372 Recruitment of PI3K subunit p110 (PIK3CA) to PI3K subunit p85 (PIK3R1) bound to p-ERBB4cyt1 homodimers
R-HSA-1306979 PIP2 to PIP3 conversion by PI3K bound to phosphorylated heterodimer of ERBB2 and ERBB4 CYT1
R-HSA-1963563 MATK (CSK homologous kinase) binds phosphorylated ERBB2
R-HSA-1963578 SHC1 binds phosphorylated ERBB2 heterodimers
R-HSA-6785636 Phosphorylated ERBB2 heterodimers bind MEMO1
R-HSA-8847995 Activated ERBB2 binds PTK6 (BRK)
R-HSA-8863804 PTPN12 dephosphorylates ERBB2 on tyrosine Y1248
R-HSA-8848005 ERBB2 promotes PTK6 autophosphorylation
R-HSA-2400009 PI3K inhibitors block PI3K catalytic activity
R-HSA-2316434 PI3K phosphorylates PIP2 to PIP3
R-HSA-1306972 RAS guanyl nucleotide exchange mediated by SOS1 bound to GRB2 in complex with phosphorylated ERBB4:ERBB2 heterodimers
R-HSA-1250195 SHC1 phosphorylation by ERBB2 heterodimers
R-HSA-1250486 Recruitment of GRB2:SOS1 to p-SHC1 in complex with phosphorylated ERBB2 heterodimers
R-HSA-6785648 MEMO1 binds RHOA:GTP:DIAPH1
R-HSA-1250383 RAS guanyl-nucleotide exchange mediated by SOS1 in complex with GRB2 and p-Y349,350-SHC1:p-ERBB4
R-HSA-1250370 Conversion of PIP2 into PIP3 by PI3K bound to p-ERBB4cyt1 homodimers
R-HSA-5672965 RAS GEFs promote RAS nucleotide exchange
R-HSA-1250463 RAS guanyl-nucleotide exchange mediated by SOS1 in complex with GRB2 and p-SHC1:Phosphorylated ERBB2 heterodimers
R-HSA-1236394 Signaling by ERBB4
R-HSA-9006934 Signaling by Receptor Tyrosine Kinases
R-HSA-1227986 Signaling by ERBB2
R-HSA-162582 Signal Transduction
R-HSA-1963642 PI3K events in ERBB2 signaling
R-HSA-1250347 SHC1 events in ERBB4 signaling
R-HSA-1251985 Nuclear signaling by ERBB4
R-HSA-1250342 PI3K events in ERBB4 signaling
R-HSA-1963640 GRB2 events in ERBB2 signaling
R-HSA-8863795 Downregulation of ERBB2 signaling
R-HSA-1250196 SHC1 events in ERBB2 signaling
R-HSA-6785631 ERBB2 Regulates Cell Motility
R-HSA-8847993 ERBB2 Activates PTK6 Signaling
R-HSA-2219530 Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-1257604 PIP3 activates AKT signaling
R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8848021 Signaling by PTK6
R-HSA-2219528 PI3K/AKT Signaling in Cancer
R-HSA-9006925 Intracellular signaling by second messengers
R-HSA-199418 Negative regulation of the PI3K/AKT network
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-9006927 Signaling by Non-Receptor Tyrosine Kinases
R-HSA-5663202 Diseases of signal transduction
R-HSA-5684996 MAPK1/MAPK3 signaling
R-HSA-1643685 Disease
R-HSA-5683057 MAPK family signaling cascades

-  Other Names for This Gene
  Alternate Gene Symbols: A6NIE8, NM_138573, NP_612640, NRG4_HUMAN, Q8WWG1
UCSC ID: uc002bbo.3
RefSeq Accession: NM_138573
Protein: Q8WWG1 (aka NRG4_HUMAN)
CCDS: CCDS10288.1

-  Gene Model Information
 
category: coding nonsense-mediated-decay: no RNA accession: NM_138573.3
exon count: 6CDS single in 3' UTR: no RNA size: 2195
ORF size: 348CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 747.00frame shift in genome: no % Coverage: 99.36
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: yes # AT/AC introns 0
selenocysteine: no end bleed into intron: 1585# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.