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P56975

- NRG3_HUMAN

UniProt

P56975 - NRG3_HUMAN

Protein

Pro-neuregulin-3, membrane-bound isoform

Gene

NRG3

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 123 (01 Oct 2014)
      Sequence version 1 (01 Dec 2000)
      Previous versions | rss
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    Functioni

    Direct ligand for the ERBB4 tyrosine kinase receptor. Binding results in ligand-stimulated tyrosine phosphorylation and activation of the receptor. Does not bind to the EGF receptor, ERBB2 or ERBB3 receptors. May be a survival factor for oligodendrocytes.2 Publications

    GO - Molecular functioni

    1. growth factor activity Source: UniProtKB
    2. receptor tyrosine kinase binding Source: UniProtKB
    3. transmembrane receptor protein tyrosine kinase activator activity Source: UniProtKB

    GO - Biological processi

    1. activation of transmembrane receptor protein tyrosine kinase activity Source: GOC
    2. mammary placode formation Source: Ensembl
    3. pattern specification process Source: Ensembl
    4. regulation of cell growth Source: UniProtKB

    Keywords - Molecular functioni

    Growth factor

    Enzyme and pathway databases

    ReactomeiREACT_115596. Signaling by ERBB4.
    REACT_115755. Signaling by ERBB2.
    REACT_115854. GRB2 events in ERBB2 signaling.
    REACT_115961. PI3K events in ERBB4 signaling.
    REACT_115993. SHC1 events in ERBB2 signaling.
    REACT_116005. SHC1 events in ERBB4 signaling.
    REACT_116008. PI3K events in ERBB2 signaling.
    REACT_116022. Nuclear signaling by ERBB4.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_75829. PIP3 activates AKT signaling.
    SignaLinkiP56975.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Pro-neuregulin-3, membrane-bound isoform
    Short name:
    Pro-NRG3
    Cleaved into the following chain:
    Neuregulin-3
    Short name:
    NRG-3
    Gene namesi
    Name:NRG3
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 10

    Organism-specific databases

    HGNCiHGNC:7999. NRG3.

    Subcellular locationi

    Chain Pro-neuregulin-3, membrane-bound isoform : Cell membrane By similarity; Single-pass type I membrane protein By similarity
    Note: Does not seem to be active.By similarity
    Isoform 3 : Cell membrane; Single-pass type I membrane protein
    Note: Isoform 3 is also proteolytically released as a soluble form.

    GO - Cellular componenti

    1. extracellular region Source: UniProtKB
    2. integral component of plasma membrane Source: UniProtKB

    Keywords - Cellular componenti

    Cell membrane, Membrane, Secreted

    Pathology & Biotechi

    Organism-specific databases

    PharmGKBiPA31778.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 720720Pro-neuregulin-3, membrane-bound isoformPRO_0000019481Add
    BLAST
    Chaini1 – 359359Neuregulin-3PRO_0000019482Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi290 ↔ 304PROSITE-ProRule annotation
    Disulfide bondi298 ↔ 317PROSITE-ProRule annotation
    Disulfide bondi319 ↔ 328PROSITE-ProRule annotation

    Post-translational modificationi

    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 By similarity. Isoform 3 is glycosylated.By similarity1 Publication

    Keywords - PTMi

    Disulfide bond, Glycoprotein

    Proteomic databases

    PaxDbiP56975.
    PRIDEiP56975.

    PTM databases

    PhosphoSiteiP56975.

    Expressioni

    Tissue specificityi

    Highly expressed in most regions of the brain with the exception of corpus callosum. Expressed at lower level in testis. Not detected in heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, ovary, small intestine, colon and peripheral blood leukocytes.

    Developmental stagei

    Isoform 3 is expressed in fetal brain but not in other fetal tissues.1 Publication

    Gene expression databases

    ArrayExpressiP56975.
    BgeeiP56975.
    CleanExiHS_NRG3.
    GenevestigatoriP56975.

    Organism-specific databases

    HPAiHPA038206.

    Interactioni

    Subunit structurei

    Interacts with ERBB4.1 Publication

    Protein-protein interaction databases

    STRINGi9606.ENSP00000361214.

    Structurei

    3D structure databases

    ProteinModelPortaliP56975.
    SMRiP56975. Positions 286-333.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 360360ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini382 – 720339CytoplasmicSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei361 – 38121Helical; Note=Internal signal sequenceSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini286 – 32944EGF-likePROSITE-ProRule annotationAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi5 – 84Poly-Ala
    Compositional biasi13 – 219Poly-Ala
    Compositional biasi26 – 349Poly-Ala
    Compositional biasi105 – 285181Ser/Thr-richAdd
    BLAST
    Compositional biasi127 – 1359Poly-Thr
    Compositional biasi252 – 2609Poly-Ser
    Compositional biasi262 – 2654Poly-Thr

    Domaini

    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.By similarity
    ERBB receptor binding is elicited entirely by the EGF-like domain.By similarity

    Sequence similaritiesi

    Belongs to the neuregulin family.Curated
    Contains 1 EGF-like domain.PROSITE-ProRule annotation

    Keywords - Domaini

    EGF-like domain, Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiNOG40523.
    HOGENOMiHOG000113852.
    HOVERGENiHBG006532.
    InParanoidiP56975.
    KOiK05457.
    OrthoDBiEOG7SR4KZ.
    PhylomeDBiP56975.
    TreeFamiTF336537.

    Family and domain databases

    InterProiIPR000742. EG-like_dom.
    IPR013032. EGF-like_CS.
    [Graphical view]
    SMARTiSM00181. EGF. 1 hit.
    [Graphical view]
    PROSITEiPS00022. EGF_1. 1 hit.
    PS01186. EGF_2. 1 hit.
    PS50026. EGF_3. 1 hit.
    [Graphical view]

    Sequences (4)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 4 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P56975-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MSEGAAAASP PGAASAAAAS AEEGTAAAAA AAAAGGGPDG GGEGAAEPPR    50
    ELRCSDCIVW NRQQTWLCVV PLFIGFIGLG LSLMLLKWIV VGSVKEYVPT 100
    DLVDSKGMGQ DPFFLSKPSS FPKAMETTTT TTSTTSPATP SAGGAASSRT 150
    PNRISTRLTT ITRAPTRFPG HRVPIRASPR STTARNTAAP ATVPSTTAPF 200
    FSSSTLGSRP PVPGTPSTQA MPSWPTAAYA TSSYLHDSTP SWTLSPFQDA 250
    ASSSSSSSSS ATTTTPETST SPKFHTTTYS TERSEHFKPC RDKDLAYCLN 300
    DGECFVIETL TGSHKHCRCK EGYQGVRCDQ FLPKTDSILS DPTDHLGIEF 350
    MESEEVYQRQ VLSISCIIFG IVIVGMFCAA FYFKSKKQAK QIQEQLKVPQ 400
    NGKSYSLKAS STMAKSENLV KSHVQLQNYS KVERHPVTAL EKMMESSFVG 450
    PQSFPEVPSP DRGSQSVKHH RSLSSCCSPG QRSGMLHRNA FRRTPPSPRS 500
    RLGGIVGPAY QQLEESRIPD QDTIPCQGIE VRKTISHLPI QLWCVERPLD 550
    LKYSSSGLKT QRNTSINMQL PSRETNPYFN SLEQKDLVGY SSTRASSVPI 600
    IPSVGLEETC LQMPGISEVK SIKWCKNSYS ADVVNVSIPV SDCLIAEQQE 650
    VKILLETVQE QIRILTDARR SEDYELASVE TEDSASENTA FLPLSPTAKS 700
    EREAQFVLRN EIQRDSALTK 720
    Length:720
    Mass (Da):77,901
    Last modified:December 1, 2000 - v1
    Checksum:iA4D6F10DDB95A693
    GO
    Isoform 2 (identifier: P56975-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         471-477: Missing.

    Show »
    Length:713
    Mass (Da):77,164
    Checksum:i1D5F8D4FA3A138FC
    GO
    Isoform 3 (identifier: P56975-3) [UniParc]FASTAAdd to Basket

    Also known as: FBNRG3

    The sequence of this isoform differs from the canonical sequence as follows:
         1-221: Missing.
         222-275: PSWPTAAYAT...PETSTSPKFH → MECGIPPTLV...LLLTNSYKFY

    Show »
    Length:499
    Mass (Da):56,034
    Checksum:i6093904545F28F94
    GO
    Isoform 4 (identifier: P56975-4) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         529-552: Missing.

    Show »
    Length:696
    Mass (Da):75,031
    Checksum:i1823F048DB30043C
    GO

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti472 – 4721S → R.
    Corresponds to variant rs2295934 [ dbSNP | Ensembl ].
    VAR_047386
    Natural varianti552 – 5521K → N.
    Corresponds to variant rs17101193 [ dbSNP | Ensembl ].
    VAR_047387

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 221221Missing in isoform 3. 1 PublicationVSP_021828Add
    BLAST
    Alternative sequencei222 – 27554PSWPT…SPKFH → MECGIPPTLVCVGRGGGLHT INIIIWYYFPSAWRTCFNIS SSVGLLLTNSYKFY in isoform 3. 1 PublicationVSP_021829Add
    BLAST
    Alternative sequencei471 – 4777Missing in isoform 2. CuratedVSP_021830
    Alternative sequencei529 – 55224Missing in isoform 4. 1 PublicationVSP_035752Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    DQ857894 mRNA. Translation: ABG77979.1.
    DQ001411 mRNA. Translation: AAY17216.1.
    AL354749
    , AL096706, AL136085, AL391478, AL513204, AL589782 Genomic DNA. Translation: CAH70641.1.
    AL136085
    , AL096706, AL354749, AL391478, AL513204, AL589782 Genomic DNA. Translation: CAH71050.1.
    AL513204
    , AL096706, AL136085, AL354749, AL391478, AL589782 Genomic DNA. Translation: CAH73645.1.
    AL391478
    , AL096706, AL136085, AL354749, AL513204, AL589782 Genomic DNA. Translation: CAI15622.1.
    AL589782
    , AL096706, AL136085, AL354749, AL391478, AL513204 Genomic DNA. Translation: CAI17213.1.
    AL096706
    , AL136085, AL354749, AL391478, AL513204, AL589782 Genomic DNA. Translation: CAI22410.1.
    CCDSiCCDS31233.1. [P56975-4]
    CCDS53547.1. [P56975-3]
    RefSeqiNP_001010848.2. NM_001010848.3. [P56975-4]
    NP_001159445.1. NM_001165973.1. [P56975-3]
    XP_005269501.1. XM_005269444.2. [P56975-1]
    UniGeneiHs.125119.

    Genome annotation databases

    EnsembliENST00000372141; ENSP00000361214; ENSG00000185737. [P56975-4]
    ENST00000372142; ENSP00000361215; ENSG00000185737. [P56975-3]
    ENST00000404547; ENSP00000384796; ENSG00000185737. [P56975-1]
    GeneIDi10718.
    KEGGihsa:10718.
    UCSCiuc001kco.2. human. [P56975-4]
    uc001kcp.2. human. [P56975-3]
    uc001kcr.2. human. [P56975-1]

    Polymorphism databases

    DMDMi9789758.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    DQ857894 mRNA. Translation: ABG77979.1 .
    DQ001411 mRNA. Translation: AAY17216.1 .
    AL354749
    , AL096706 , AL136085 , AL391478 , AL513204 , AL589782 Genomic DNA. Translation: CAH70641.1 .
    AL136085
    , AL096706 , AL354749 , AL391478 , AL513204 , AL589782 Genomic DNA. Translation: CAH71050.1 .
    AL513204
    , AL096706 , AL136085 , AL354749 , AL391478 , AL589782 Genomic DNA. Translation: CAH73645.1 .
    AL391478
    , AL096706 , AL136085 , AL354749 , AL513204 , AL589782 Genomic DNA. Translation: CAI15622.1 .
    AL589782
    , AL096706 , AL136085 , AL354749 , AL391478 , AL513204 Genomic DNA. Translation: CAI17213.1 .
    AL096706
    , AL136085 , AL354749 , AL391478 , AL513204 , AL589782 Genomic DNA. Translation: CAI22410.1 .
    CCDSi CCDS31233.1. [P56975-4 ]
    CCDS53547.1. [P56975-3 ]
    RefSeqi NP_001010848.2. NM_001010848.3. [P56975-4 ]
    NP_001159445.1. NM_001165973.1. [P56975-3 ]
    XP_005269501.1. XM_005269444.2. [P56975-1 ]
    UniGenei Hs.125119.

    3D structure databases

    ProteinModelPortali P56975.
    SMRi P56975. Positions 286-333.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    STRINGi 9606.ENSP00000361214.

    PTM databases

    PhosphoSitei P56975.

    Polymorphism databases

    DMDMi 9789758.

    Proteomic databases

    PaxDbi P56975.
    PRIDEi P56975.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000372141 ; ENSP00000361214 ; ENSG00000185737 . [P56975-4 ]
    ENST00000372142 ; ENSP00000361215 ; ENSG00000185737 . [P56975-3 ]
    ENST00000404547 ; ENSP00000384796 ; ENSG00000185737 . [P56975-1 ]
    GeneIDi 10718.
    KEGGi hsa:10718.
    UCSCi uc001kco.2. human. [P56975-4 ]
    uc001kcp.2. human. [P56975-3 ]
    uc001kcr.2. human. [P56975-1 ]

    Organism-specific databases

    CTDi 10718.
    GeneCardsi GC10P083625.
    HGNCi HGNC:7999. NRG3.
    HPAi HPA038206.
    MIMi 605533. gene.
    neXtProti NX_P56975.
    PharmGKBi PA31778.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG40523.
    HOGENOMi HOG000113852.
    HOVERGENi HBG006532.
    InParanoidi P56975.
    KOi K05457.
    OrthoDBi EOG7SR4KZ.
    PhylomeDBi P56975.
    TreeFami TF336537.

    Enzyme and pathway databases

    Reactomei REACT_115596. Signaling by ERBB4.
    REACT_115755. Signaling by ERBB2.
    REACT_115854. GRB2 events in ERBB2 signaling.
    REACT_115961. PI3K events in ERBB4 signaling.
    REACT_115993. SHC1 events in ERBB2 signaling.
    REACT_116005. SHC1 events in ERBB4 signaling.
    REACT_116008. PI3K events in ERBB2 signaling.
    REACT_116022. Nuclear signaling by ERBB4.
    REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_75829. PIP3 activates AKT signaling.
    SignaLinki P56975.

    Miscellaneous databases

    GeneWikii NRG3.
    GenomeRNAii 10718.
    NextBioi 40693.
    PROi P56975.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P56975.
    Bgeei P56975.
    CleanExi HS_NRG3.
    Genevestigatori P56975.

    Family and domain databases

    InterProi IPR000742. EG-like_dom.
    IPR013032. EGF-like_CS.
    [Graphical view ]
    SMARTi SM00181. EGF. 1 hit.
    [Graphical view ]
    PROSITEi PS00022. EGF_1. 1 hit.
    PS01186. EGF_2. 1 hit.
    PS50026. EGF_3. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4."
      Zhang D., Sliwkowski M.X., Mark M., Frantz G., Akita R., Sun Y., Hillan K., Crowley C., Brush J., Godowski P.J.
      Proc. Natl. Acad. Sci. U.S.A. 94:9562-9567(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION.
      Tissue: Fetal brain.
    2. "Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival."
      Carteron C., Ferrer-Montiel A.V., Cabedo H.
      J. Cell Sci. 119:898-909(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), DEVELOPMENTAL STAGE, SUBCELLULAR LOCATION, GLYCOSYLATION, FUNCTION.
      Tissue: Fetal brain.
    3. "Bi-directional signalling by NRG-3 cytoplasmic domain."
      Tiao J.Y., Busfield S.J.
      Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
    4. "The DNA sequence and comparative analysis of human chromosome 10."
      Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J.
      , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.
      Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    5. "Ligand discrimination in signaling through an ErbB4 receptor homodimer."
      Sweeney C., Lai C., Riese D.J. II, Diamonti A.J., Cantley L.C., Carraway K.L. III
      J. Biol. Chem. 275:19803-19807(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ERBB4.

    Entry informationi

    Entry nameiNRG3_HUMAN
    AccessioniPrimary (citable) accession number: P56975
    Secondary accession number(s): A4D7U1, Q0PEH2, Q5VYH3
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 1, 2000
    Last sequence update: December 1, 2000
    Last modified: October 1, 2014
    This is version 123 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 10
      Human chromosome 10: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3