NRG4_HUMAN
ID NRG4_HUMAN Reviewed; 115 AA.
AC Q8WWG1; A6NIE8;
DT 01-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2002, sequence version 1.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=Pro-neuregulin-4, membrane-bound isoform;
DE Short=Pro-NRG4;
DE Contains:
DE RecName: Full=Neuregulin-4;
DE Short=NRG-4;
GN Name=NRG4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
CC -!- FUNCTION: Low affinity ligand for the ERBB4 tyrosine kinase receptor.
CC Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in
CC ligand-stimulated tyrosine phosphorylation and activation of the ERBB
CC receptors. Does not bind to the ERBB1, ERBB2 and ERBB3 receptors (By
CC similarity). {ECO:0000250}.
CC -!- SUBUNIT: Interacts with ERBB4. {ECO:0000250}.
CC -!- INTERACTION:
CC Q8WWG1; Q8N5K1: CISD2; NbExp=3; IntAct=EBI-8637292, EBI-1045797;
CC Q8WWG1; Q9Y282: ERGIC3; NbExp=3; IntAct=EBI-8637292, EBI-781551;
CC Q8WWG1; Q969F0: FATE1; NbExp=7; IntAct=EBI-8637292, EBI-743099;
CC Q8WWG1; Q8TAF8: LHFPL5; NbExp=3; IntAct=EBI-8637292, EBI-2820517;
CC -!- SUBCELLULAR LOCATION: [Pro-neuregulin-4, membrane-bound isoform]: Cell
CC membrane {ECO:0000250}; Single-pass type I membrane protein
CC {ECO:0000250}. Note=Does not seem to be active. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: [Neuregulin-4]: Secreted {ECO:0000250}.
CC -!- DOMAIN: The cytoplasmic domain may be involved in the regulation of
CC trafficking and proteolytic processing. Regulation of the proteolytic
CC processing involves initial intracellular domain dimerization (By
CC similarity). {ECO:0000250}.
CC -!- DOMAIN: ERBB receptor binding is elicited entirely by the EGF-like
CC domain. {ECO:0000250}.
CC -!- PTM: Proteolytic cleavage close to the plasma membrane on the external
CC face leads to the release of the soluble growth factor form.
CC {ECO:0000250}.
CC -!- PTM: Extensive glycosylation precedes the proteolytic cleavage.
CC {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the neuregulin family. {ECO:0000305}.
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DR EMBL; AC087456; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471136; EAW99227.1; -; Genomic_DNA.
DR EMBL; BC017568; AAH17568.1; -; mRNA.
DR CCDS; CCDS10288.1; -.
DR RefSeq; NP_612640.1; NM_138573.3.
DR RefSeq; XP_016877434.1; XM_017021945.1.
DR RefSeq; XP_016877435.1; XM_017021946.1.
DR RefSeq; XP_016877436.1; XM_017021947.1.
DR RefSeq; XP_016877437.1; XM_017021948.1.
DR AlphaFoldDB; Q8WWG1; -.
DR SMR; Q8WWG1; -.
DR BioGRID; 126957; 5.
DR IntAct; Q8WWG1; 5.
DR MINT; Q8WWG1; -.
DR STRING; 9606.ENSP00000378367; -.
DR GlyGen; Q8WWG1; 1 site.
DR BioMuta; NRG4; -.
DR DMDM; 28201832; -.
DR MassIVE; Q8WWG1; -.
DR PaxDb; Q8WWG1; -.
DR PeptideAtlas; Q8WWG1; -.
DR PRIDE; Q8WWG1; -.
DR Antibodypedia; 2623; 230 antibodies from 23 providers.
DR DNASU; 145957; -.
DR Ensembl; ENST00000394907.8; ENSP00000378367.3; ENSG00000169752.17.
DR Ensembl; ENST00000566417.5; ENSP00000457335.1; ENSG00000169752.17.
DR GeneID; 145957; -.
DR KEGG; hsa:145957; -.
DR MANE-Select; ENST00000394907.8; ENSP00000378367.3; NM_138573.4; NP_612640.1.
DR UCSC; uc002bbo.5; human.
DR CTD; 145957; -.
DR DisGeNET; 145957; -.
DR GeneCards; NRG4; -.
DR HGNC; HGNC:29862; NRG4.
DR HPA; ENSG00000169752; Group enriched (brain, retina).
DR MIM; 610894; gene.
DR neXtProt; NX_Q8WWG1; -.
DR OpenTargets; ENSG00000169752; -.
DR PharmGKB; PA142671246; -.
DR VEuPathDB; HostDB:ENSG00000169752; -.
DR eggNOG; ENOG502S5EK; Eukaryota.
DR GeneTree; ENSGT00390000014815; -.
DR InParanoid; Q8WWG1; -.
DR OMA; EYWKVQS; -.
DR OrthoDB; 1521132at2759; -.
DR PhylomeDB; Q8WWG1; -.
DR PathwayCommons; Q8WWG1; -.
DR Reactome; R-HSA-1227986; Signaling by ERBB2.
DR Reactome; R-HSA-1236394; Signaling by ERBB4.
DR Reactome; R-HSA-1250196; SHC1 events in ERBB2 signaling.
DR Reactome; R-HSA-1250342; PI3K events in ERBB4 signaling.
DR Reactome; R-HSA-1250347; SHC1 events in ERBB4 signaling.
DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4.
DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-HSA-1963640; GRB2 events in ERBB2 signaling.
DR Reactome; R-HSA-1963642; PI3K events in ERBB2 signaling.
DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-6785631; ERBB2 Regulates Cell Motility.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-8847993; ERBB2 Activates PTK6 Signaling.
DR Reactome; R-HSA-8863795; Downregulation of ERBB2 signaling.
DR Reactome; R-HSA-9664565; Signaling by ERBB2 KD Mutants.
DR Reactome; R-HSA-9665686; Signaling by ERBB2 TMD/JMD mutants.
DR SignaLink; Q8WWG1; -.
DR SIGNOR; Q8WWG1; -.
DR BioGRID-ORCS; 145957; 8 hits in 1065 CRISPR screens.
DR ChiTaRS; NRG4; human.
DR GeneWiki; NRG4; -.
DR GenomeRNAi; 145957; -.
DR Pharos; Q8WWG1; Tbio.
DR PRO; PR:Q8WWG1; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q8WWG1; protein.
DR Bgee; ENSG00000169752; Expressed in body of pancreas and 98 other tissues.
DR ExpressionAtlas; Q8WWG1; baseline and differential.
DR Genevisible; Q8WWG1; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW.
DR GO; GO:0048018; F:receptor ligand activity; IDA:MGI.
DR GO; GO:0038138; P:ERBB4-ERBB4 signaling pathway; IEA:Ensembl.
DR GO; GO:0007399; P:nervous system development; IEA:InterPro.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR040180; Neuregulin.
DR PANTHER; PTHR11100; PTHR11100; 1.
DR Pfam; PF00008; EGF; 1.
DR SMART; SM00181; EGF; 1.
DR PROSITE; PS00022; EGF_1; 1.
DR PROSITE; PS50026; EGF_3; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Disulfide bond; EGF-like domain; Glycoprotein;
KW Growth factor; Membrane; Reference proteome; Secreted; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..115
FT /note="Pro-neuregulin-4, membrane-bound isoform"
FT /id="PRO_0000019485"
FT CHAIN 1..61
FT /note="Neuregulin-4"
FT /id="PRO_0000019486"
FT TOPO_DOM 1..62
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 63..83
FT /note="Helical; Note=Internal signal sequence"
FT /evidence="ECO:0000255"
FT TOPO_DOM 84..115
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 5..46
FT /note="EGF-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT CARBOHYD 39
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 9..23
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 17..34
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 36..45
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
SQ SEQUENCE 115 AA; 12722 MW; 72F962E2D0F37AC3 CRC64;
MPTDHEEPCG PSHKSFCLNG GLCYVIPTIP SPFCRCVENY TGARCEEVFL PGSSIQTKSN
LFEAFVALAV LVTLIIGAFY FLCRKGHFQR ASSVQYDINL VETSSTSAHH SHEQH
