NRG3_HUMAN
ID NRG3_HUMAN Reviewed; 720 AA.
AC P56975; A4D7U1; Q0PEH2; Q5VYH3;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 1.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Pro-neuregulin-3, membrane-bound isoform;
DE Short=Pro-NRG3;
DE Contains:
DE RecName: Full=Neuregulin-3;
DE Short=NRG-3;
DE Flags: Precursor;
GN Name=NRG3;
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 [MRNA] (ISOFORM 1), AND FUNCTION.
RC TISSUE=Fetal brain;
RX PubMed=9275162; DOI=10.1073/pnas.94.18.9562;
RA Zhang D., Sliwkowski M.X., Mark M., Frantz G., Akita R., Sun Y., Hillan K.,
RA Crowley C., Brush J., Godowski P.J.;
RT "Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and
RT activates ErbB4.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:9562-9567(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), DEVELOPMENTAL STAGE, SUBCELLULAR
RP LOCATION, GLYCOSYLATION, AND FUNCTION.
RC TISSUE=Fetal brain;
RX PubMed=16478787; DOI=10.1242/jcs.02799;
RA Carteron C., Ferrer-Montiel A.V., Cabedo H.;
RT "Characterization of a neural-specific splicing form of the human
RT neuregulin 3 gene involved in oligodendrocyte survival.";
RL J. Cell Sci. 119:898-909(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA Tiao J.Y., Busfield S.J.;
RT "Bi-directional signalling by NRG-3 cytoplasmic domain.";
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [5]
RP INTERACTION WITH ERBB4.
RX PubMed=10867024; DOI=10.1074/jbc.c901015199;
RA Sweeney C., Lai C., Riese D.J. II, Diamonti A.J., Cantley L.C.,
RA Carraway K.L. III;
RT "Ligand discrimination in signaling through an ErbB4 receptor homodimer.";
RL J. Biol. Chem. 275:19803-19807(2000).
CC -!- FUNCTION: Direct ligand for the ERBB4 tyrosine kinase receptor. Binding
CC results in ligand-stimulated tyrosine phosphorylation and activation of
CC the receptor. Does not bind to the EGF receptor, ERBB2 or ERBB3
CC receptors. May be a survival factor for oligodendrocytes.
CC {ECO:0000269|PubMed:16478787, ECO:0000269|PubMed:9275162}.
CC -!- SUBUNIT: Interacts with ERBB4. {ECO:0000269|PubMed:10867024}.
CC -!- SUBCELLULAR LOCATION: [Pro-neuregulin-3, 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-3]: Secreted {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Cell membrane; Single-pass type I
CC membrane protein. Note=Isoform 3 is also proteolytically released as a
CC soluble form.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P56975-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P56975-2; Sequence=VSP_021830;
CC Name=3; Synonyms=FBNRG3;
CC IsoId=P56975-3; Sequence=VSP_021828, VSP_021829;
CC Name=4;
CC IsoId=P56975-4; Sequence=VSP_035752;
CC -!- TISSUE SPECIFICITY: Highly expressed in most regions of the brain with
CC the exception of corpus callosum. Expressed at lower level in testis.
CC Not detected in heart, placenta, lung, liver, skeletal muscle, kidney,
CC pancreas, spleen, thymus, prostate, ovary, small intestine, colon and
CC peripheral blood leukocytes.
CC -!- DEVELOPMENTAL STAGE: Isoform 3 is expressed in fetal brain but not in
CC other fetal tissues. {ECO:0000269|PubMed:16478787}.
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 -!- PTM: Extensive glycosylation precedes the proteolytic cleavage (By
CC similarity). Isoform 3 is glycosylated. {ECO:0000250,
CC ECO:0000269|PubMed:16478787}.
CC -!- SIMILARITY: Belongs to the neuregulin family. {ECO:0000305}.
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DR EMBL; DQ857894; ABG77979.1; -; mRNA.
DR EMBL; DQ001411; AAY17216.1; -; mRNA.
DR EMBL; AL096706; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL136085; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL354749; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL391478; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL513204; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL589782; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS31233.1; -. [P56975-4]
DR CCDS; CCDS53547.1; -. [P56975-3]
DR RefSeq; NP_001010848.2; NM_001010848.3. [P56975-4]
DR RefSeq; NP_001159445.1; NM_001165973.1. [P56975-3]
DR RefSeq; XP_005269501.1; XM_005269444.4.
DR AlphaFoldDB; P56975; -.
DR SMR; P56975; -.
DR BioGRID; 115944; 2.
DR IntAct; P56975; 1.
DR STRING; 9606.ENSP00000361214; -.
DR iPTMnet; P56975; -.
DR PhosphoSitePlus; P56975; -.
DR BioMuta; NRG3; -.
DR DMDM; 9789758; -.
DR jPOST; P56975; -.
DR MassIVE; P56975; -.
DR PaxDb; P56975; -.
DR PeptideAtlas; P56975; -.
DR PRIDE; P56975; -.
DR Antibodypedia; 30013; 226 antibodies from 36 providers.
DR DNASU; 10718; -.
DR Ensembl; ENST00000372141.7; ENSP00000361214.2; ENSG00000185737.13. [P56975-4]
DR Ensembl; ENST00000372142.6; ENSP00000361215.2; ENSG00000185737.13. [P56975-3]
DR Ensembl; ENST00000404547.5; ENSP00000384796.1; ENSG00000185737.13. [P56975-1]
DR GeneID; 10718; -.
DR KEGG; hsa:10718; -.
DR MANE-Select; ENST00000372141.7; ENSP00000361214.2; NM_001010848.4; NP_001010848.2. [P56975-4]
DR UCSC; uc001kco.3; human. [P56975-1]
DR CTD; 10718; -.
DR DisGeNET; 10718; -.
DR GeneCards; NRG3; -.
DR HGNC; HGNC:7999; NRG3.
DR HPA; ENSG00000185737; Tissue enhanced (brain).
DR MIM; 605533; gene.
DR neXtProt; NX_P56975; -.
DR OpenTargets; ENSG00000185737; -.
DR PharmGKB; PA31778; -.
DR VEuPathDB; HostDB:ENSG00000185737; -.
DR eggNOG; ENOG502QS97; Eukaryota.
DR GeneTree; ENSGT00940000156754; -.
DR HOGENOM; CLU_395836_0_0_1; -.
DR InParanoid; P56975; -.
DR OrthoDB; 583156at2759; -.
DR PhylomeDB; P56975; -.
DR TreeFam; TF336537; -.
DR PathwayCommons; P56975; -.
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; P56975; -.
DR SIGNOR; P56975; -.
DR BioGRID-ORCS; 10718; 14 hits in 1064 CRISPR screens.
DR ChiTaRS; NRG3; human.
DR GeneWiki; NRG3; -.
DR GenomeRNAi; 10718; -.
DR Pharos; P56975; Tbio.
DR PRO; PR:P56975; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; P56975; protein.
DR Bgee; ENSG00000185737; Expressed in endothelial cell and 119 other tissues.
DR ExpressionAtlas; P56975; baseline and differential.
DR Genevisible; P56975; HS.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:MGI.
DR GO; GO:0098978; C:glutamatergic synapse; IMP:SynGO.
DR GO; GO:0005887; C:integral component of plasma membrane; NAS:UniProtKB.
DR GO; GO:0045499; F:chemorepellent activity; IBA:GO_Central.
DR GO; GO:0008083; F:growth factor activity; NAS:UniProtKB.
DR GO; GO:0048018; F:receptor ligand activity; IDA:MGI.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; NAS:UniProtKB.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0030297; F:transmembrane receptor protein tyrosine kinase activator activity; NAS:UniProtKB.
DR GO; GO:0048513; P:animal organ development; IBA:GO_Central.
DR GO; GO:0021842; P:chemorepulsion involved in interneuron migration from the subpallium to the cortex; IEA:Ensembl.
DR GO; GO:0038130; P:ERBB4 signaling pathway; IDA:MGI.
DR GO; GO:0038138; P:ERBB4-ERBB4 signaling pathway; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0060596; P:mammary placode formation; IEA:Ensembl.
DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IMP:SynGO.
DR GO; GO:2001223; P:negative regulation of neuron migration; IEA:Ensembl.
DR GO; GO:0007389; P:pattern specification process; IEA:Ensembl.
DR GO; GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR040180; Neuregulin.
DR PANTHER; PTHR11100; PTHR11100; 2.
DR PROSITE; PS00022; EGF_1; 1.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Disulfide bond; EGF-like domain;
KW Glycoprotein; Growth factor; Membrane; Reference proteome; Secreted;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..720
FT /note="Pro-neuregulin-3, membrane-bound isoform"
FT /id="PRO_0000019481"
FT CHAIN 1..359
FT /note="Neuregulin-3"
FT /id="PRO_0000019482"
FT TOPO_DOM 1..360
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 361..381
FT /note="Helical; Note=Internal signal sequence"
FT /evidence="ECO:0000255"
FT TOPO_DOM 382..720
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 286..329
FT /note="EGF-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT REGION 28..48
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 119..223
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 246..280
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 451..481
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 121..163
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 179..223
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 246..278
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT DISULFID 290..304
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 298..317
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DISULFID 319..328
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT VAR_SEQ 1..221
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16478787"
FT /id="VSP_021828"
FT VAR_SEQ 222..275
FT /note="PSWPTAAYATSSYLHDSTPSWTLSPFQDAASSSSSSSSSATTTTPETSTSPK
FT FH -> MECGIPPTLVCVGRGGGLHTINIIIWYYFPSAWRTCFNISSSVGLLLTNSYKF
FT Y (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16478787"
FT /id="VSP_021829"
FT VAR_SEQ 471..477
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_021830"
FT VAR_SEQ 529..552
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_035752"
FT VARIANT 472
FT /note="S -> R (in dbSNP:rs2295934)"
FT /id="VAR_047386"
FT VARIANT 552
FT /note="K -> N (in dbSNP:rs17101193)"
FT /id="VAR_047387"
SQ SEQUENCE 720 AA; 77901 MW; A4D6F10DDB95A693 CRC64;
MSEGAAAASP PGAASAAAAS AEEGTAAAAA AAAAGGGPDG GGEGAAEPPR ELRCSDCIVW
NRQQTWLCVV PLFIGFIGLG LSLMLLKWIV VGSVKEYVPT DLVDSKGMGQ DPFFLSKPSS
FPKAMETTTT TTSTTSPATP SAGGAASSRT PNRISTRLTT ITRAPTRFPG HRVPIRASPR
STTARNTAAP ATVPSTTAPF FSSSTLGSRP PVPGTPSTQA MPSWPTAAYA TSSYLHDSTP
SWTLSPFQDA ASSSSSSSSS ATTTTPETST SPKFHTTTYS TERSEHFKPC RDKDLAYCLN
DGECFVIETL TGSHKHCRCK EGYQGVRCDQ FLPKTDSILS DPTDHLGIEF MESEEVYQRQ
VLSISCIIFG IVIVGMFCAA FYFKSKKQAK QIQEQLKVPQ NGKSYSLKAS STMAKSENLV
KSHVQLQNYS KVERHPVTAL EKMMESSFVG PQSFPEVPSP DRGSQSVKHH RSLSSCCSPG
QRSGMLHRNA FRRTPPSPRS RLGGIVGPAY QQLEESRIPD QDTIPCQGIE VRKTISHLPI
QLWCVERPLD LKYSSSGLKT QRNTSINMQL PSRETNPYFN SLEQKDLVGY SSTRASSVPI
IPSVGLEETC LQMPGISEVK SIKWCKNSYS ADVVNVSIPV SDCLIAEQQE VKILLETVQE
QIRILTDARR SEDYELASVE TEDSASENTA FLPLSPTAKS EREAQFVLRN EIQRDSALTK
