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   24-JAN-2024, entry version 186.
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   CCDS; CCDS91287.1; -. [P56975-1]
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   GlyGen; P56975; 6 sites, 1 O-linked glycan (6 sites).
DR   iPTMnet; P56975; -.
DR   PhosphoSitePlus; P56975; -.
DR   BioMuta; NRG3; -.
DR   DMDM; 9789758; -.
DR   jPOST; P56975; -.
DR   MassIVE; P56975; -.
DR   PaxDb; 9606-ENSP00000361214; -.
DR   PeptideAtlas; P56975; -.
DR   ProteomicsDB; 56963; -. [P56975-1]
DR   ProteomicsDB; 56964; -. [P56975-2]
DR   ProteomicsDB; 56965; -. [P56975-3]
DR   ProteomicsDB; 56966; -. [P56975-4]
DR   Antibodypedia; 30013; 265 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   AGR; HGNC:7999; -.
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   OMA; WCKNSCS; -.
DR   OrthoDB; 5355912at2759; -.
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 1140 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 120 other cell types or tissues.
DR   ExpressionAtlas; P56975; baseline and differential.
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; IDA:SynGO.
DR   GO; GO:0005886; C: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: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; IDA: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   GO; GO:0007416; P:synapse assembly; IEA:Ensembl.
DR   Gene3D; 2.10.25.10; Laminin; 1.
DR   InterPro; IPR000742; EGF-like_dom.
DR   InterPro; IPR040180; Neuregulin.
DR   PANTHER; PTHR11100; HEREGULIN-NEUREGULIN FAMILY MEMBER; 1.
DR   PANTHER; PTHR11100:SF18; PRO-NEUREGULIN-3, MEMBRANE-BOUND ISOFORM; 1.
DR   SUPFAM; SSF57196; EGF/Laminin; 1.
DR   PROSITE; PS00022; EGF_1; 1.
DR   PROSITE; PS01186; EGF_2; 1.
DR   PROSITE; PS50026; EGF_3; 1.
DR   Genevisible; P56975; HS.
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
//