GenomeNet

Database: UniProt
Entry: P43322
LinkDB: P43322
Original site: P43322 
ID   NRG1_RAT                Reviewed;         662 AA.
AC   P43322; P43323; P43324; P43325; P43326; P43327; P43328;
DT   01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   13-FEB-2019, entry version 161.
DE   RecName: Full=Pro-neuregulin-1, membrane-bound isoform;
DE            Short=Pro-NRG1;
DE   Contains:
DE     RecName: Full=Neuregulin-1;
DE     AltName: Full=Acetylcholine receptor-inducing activity;
DE              Short=ARIA;
DE     AltName: Full=Glial growth factor;
DE     AltName: Full=Heregulin;
DE              Short=HRG;
DE     AltName: Full=Neu differentiation factor;
DE     AltName: Full=Sensory and motor neuron-derived factor;
DE   Flags: Precursor;
GN   Name=Nrg1; Synonyms=Ndf;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
OC   Muroidea; Muridae; Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND ALTERNATIVE SPLICING.
RC   TISSUE=Fibroblast;
RX   PubMed=7509448; DOI=10.1128/MCB.14.3.1909;
RA   Wen D., Suggs S.V., Karunagaran D., Liu N., Cupples R.L., Luo Y.,
RA   Janssen A.M., Ben-Baruch N., Trollinger D.B., Jacobsen V.L.,
RA   Meng S.-Y., Lu H.S., Hu S., Chang D., Yang W., Yanigahara D.,
RA   Koski R.A., Yarden Y.;
RT   "Structural and functional aspects of the multiplicity of Neu
RT   differentiation factors.";
RL   Mol. Cell. Biol. 14:1909-1919(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA2C), AND PARTIAL PROTEIN
RP   SEQUENCE.
RC   TISSUE=Fibroblast;
RX   PubMed=1349853; DOI=10.1016/0092-8674(92)90456-M;
RA   Wen D., Peles E., Cupples R., Suggs S.V., Bacus S.S., Luo Y.,
RA   Trail G., Hu S., Silbiger S.M., Levy R.B., Koski R.A., Lu H.S.,
RA   Yarden Y.;
RT   "Neu differentiation factor: a transmembrane glycoprotein containing
RT   an EGF domain and an immunoglobulin homology unit.";
RL   Cell 69:559-572(1992).
RN   [3]
RP   PROTEIN SEQUENCE OF 14-36.
RX   PubMed=1348215; DOI=10.1016/0092-8674(92)90131-U;
RA   Peles E., Bacus S.S., Koski R.A., Lu H.S., Wen D., Ogden S.G.,
RA   Levy R.B., Yarden Y.;
RT   "Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein
RT   that induces differentiation of mammary tumor cells.";
RL   Cell 69:205-216(1992).
RN   [4]
RP   REGULATION OF PROCESSING (ISOFORM ALPHA2C).
RX   PubMed=9852099; DOI=10.1074/jbc.273.51.34335;
RA   Liu X., Hwang H., Cao L., Wen D., Liu N., Graham R.M., Zhou M.;
RT   "Release of the neuregulin functional polypeptide requires its
RT   cytoplasmic tail.";
RL   J. Biol. Chem. 273:34335-34340(1998).
RN   [5]
RP   INTERACTION WITH LIMK1.
RX   PubMed=9685409; DOI=10.1074/jbc.273.32.20525;
RA   Wang J.Y., Frenzel K.E., Wen D., Falls D.L.;
RT   "Transmembrane neuregulins interact with LIM kinase 1, a cytoplasmic
RT   protein kinase implicated in development of visuospatial cognition.";
RL   J. Biol. Chem. 273:20525-20534(1998).
RN   [6]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=16641100; DOI=10.1073/pnas.0600895103;
RA   Hoffert J.D., Pisitkun T., Wang G., Shen R.-F., Knepper M.A.;
RT   "Quantitative phosphoproteomics of vasopressin-sensitive renal cells:
RT   regulation of aquaporin-2 phosphorylation at two sites.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:7159-7164(2006).
RN   [7]
RP   FUNCTION.
RX   PubMed=17250808; DOI=10.1016/j.bbrc.2007.01.009;
RA   Liu Y., Tao Y.M., Woo R.S., Xiong W.C., Mei L.;
RT   "Stimulated ErbB4 internalization is necessary for neuregulin
RT   signaling in neurons.";
RL   Biochem. Biophys. Res. Commun. 354:505-510(2007).
CC   -!- FUNCTION: Direct ligand for ERBB3 and ERBB4 tyrosine kinase
CC       receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors,
CC       resulting in ligand-stimulated tyrosine phosphorylation and
CC       activation of the ERBB receptors. The multiple isoforms perform
CC       diverse functions such as inducing growth and differentiation of
CC       epithelial, glial, neuronal, and skeletal muscle cells; inducing
CC       expression of acetylcholine receptor in synaptic vesicles during
CC       the formation of the neuromuscular junction; stimulating
CC       lobuloalveolar budding and milk production in the mammary gland
CC       and inducing differentiation of mammary tumor cells; stimulating
CC       Schwann cell proliferation; implication in the development of the
CC       myocardium such as trabeculation of the developing heart. Binds to
CC       ERBB4 and ERBB3. Acts as a ligand for integrins and binds (via EGF
CC       domain) to integrins ITGAV:ITGB3 or ITGA6:ITGB4. Its binding to
CC       integrins and subsequent ternary complex formation with integrins
CC       and ERRB3 are essential for NRG1-ERBB signaling (By similarity).
CC       Induces the phosphorylation and activation of MAPK3/ERK1,
CC       MAPK1/ERK2 and AKT1, and ligand-dependent ERBB4 endocytosis is
CC       essential for the NRG1-mediated activation of these kinases in
CC       neurons (PubMed:17250808). {ECO:0000250|UniProtKB:Q02297,
CC       ECO:0000269|PubMed:17250808}.
CC   -!- SUBUNIT: The cytoplasmic domain interacts with the LIM domain
CC       region of LIMK1 (PubMed:9685409). Forms a ternary complex with
CC       ERBB3 and ITGAV:ITGB3 or ITGA6:ITGB4 (By similarity).
CC       {ECO:0000250|UniProtKB:Q02297, ECO:0000269|PubMed:9685409}.
CC   -!- SUBCELLULAR LOCATION: Pro-neuregulin-1, membrane-bound isoform:
CC       Cell membrane; Single-pass type I membrane protein. Note=Does not
CC       seem to be active.
CC   -!- SUBCELLULAR LOCATION: Neuregulin-1: Secreted.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=8;
CC         Comment=Additional isoforms seem to exist.;
CC       Name=Beta4; Synonyms=NDF42A;
CC         IsoId=P43322-1; Sequence=Displayed;
CC       Name=Alpha2A; Synonyms=NDF38;
CC         IsoId=P43322-2; Sequence=VSP_003436;
CC       Name=Alpha2B; Synonyms=NDF19;
CC         IsoId=P43322-3; Sequence=VSP_003436, VSP_003443, VSP_003444;
CC       Name=Alpha2C; Synonyms=NDF44;
CC         IsoId=P43322-4; Sequence=VSP_003436, VSP_003442;
CC       Name=Beta1;
CC         IsoId=P43322-5; Sequence=VSP_003437;
CC       Name=Beta2; Synonyms=NDF40;
CC         IsoId=P43322-6; Sequence=VSP_003440, VSP_003441;
CC       Name=BetA2A; Synonyms=NDF22;
CC         IsoId=P43322-7; Sequence=VSP_003440;
CC       Name=Beta3; Synonyms=NDF4;
CC         IsoId=P43322-8; Sequence=VSP_003438, VSP_003439;
CC   -!- TISSUE SPECIFICITY: Widely expressed. Most tissues contain isoform
CC       alpha2A and isoform alpha2B. Isoform Alpha2 and isoform beta2 are
CC       the predominant forms in mesenchymal and non-neuronal organs.
CC       Isoform Beta1 is enriched in brain and spinal cord, but not in
CC       muscle and heart. Isoform Alpha2C is highly expressed in spinal
CC       cord, moderately in lung, brain, ovary, and stomach, in low
CC       amounts in the kidney, skin and heart and not detected in the
CC       liver, spleen, and placenta.
CC   -!- DOMAIN: The cytoplasmic domain may be involved in the regulation
CC       of trafficking and proteolytic processing. Regulation of the
CC       proteolytic processing involves initial intracellular domain
CC       dimerization.
CC   -!- DOMAIN: ERBB receptor binding is elicited entirely by the EGF-like
CC       domain.
CC   -!- PTM: Proteolytic cleavage close to the plasma membrane on the
CC       external face leads to the release of the soluble growth factor
CC       form.
CC   -!- PTM: N- and O-glycosylated (By similarity). Extensive
CC       glycosylation precedes the proteolytic cleavage. {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the neuregulin family. {ECO:0000305}.
DR   EMBL; U02315; AAA19940.1; -; mRNA.
DR   EMBL; U02316; AAA19941.1; -; mRNA.
DR   EMBL; U02317; AAA19942.1; -; mRNA.
DR   EMBL; U02318; AAA19943.1; -; mRNA.
DR   EMBL; U02319; AAA19944.1; -; mRNA.
DR   EMBL; U02320; AAA19945.1; -; mRNA.
DR   EMBL; U02321; AAA19946.1; -; mRNA.
DR   EMBL; U02322; AAA19947.1; -; mRNA.
DR   EMBL; U02323; AAA19948.1; -; mRNA.
DR   EMBL; U02324; AAA19949.1; -; mRNA.
DR   EMBL; M92430; -; NOT_ANNOTATED_CDS; mRNA.
DR   PIR; I61718; I61718.
DR   PIR; I61719; I61719.
DR   PIR; I61722; I61722.
DR   RefSeq; NP_001258052.1; NM_001271123.1. [P43322-8]
DR   UniGene; Rn.37438; -.
DR   ProteinModelPortal; P43322; -.
DR   SMR; P43322; -.
DR   STRING; 10116.ENSRNOP00000014268; -.
DR   iPTMnet; P43322; -.
DR   PhosphoSitePlus; P43322; -.
DR   PaxDb; P43322; -.
DR   PRIDE; P43322; -.
DR   GeneID; 112400; -.
DR   KEGG; rno:112400; -.
DR   UCSC; RGD:621341; rat. [P43322-1]
DR   CTD; 3084; -.
DR   RGD; 621341; Nrg1.
DR   eggNOG; ENOG410IEU9; Eukaryota.
DR   eggNOG; ENOG4110ST7; LUCA.
DR   HOVERGEN; HBG006531; -.
DR   InParanoid; P43322; -.
DR   KO; K05455; -.
DR   OrthoDB; 313400at2759; -.
DR   PhylomeDB; P43322; -.
DR   PRO; PR:P43322; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0005615; C:extracellular space; IDA:RGD.
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:0045202; C:synapse; IDA:RGD.
DR   GO; GO:0043125; F:ErbB-3 class receptor binding; ISS:UniProtKB.
DR   GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW.
DR   GO; GO:0005178; F:integrin binding; ISS:UniProtKB.
DR   GO; GO:0030296; F:protein tyrosine kinase activator activity; IBA:GO_Central.
DR   GO; GO:0030971; F:receptor tyrosine kinase binding; IDA:MGI.
DR   GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR   GO; GO:0000187; P:activation of MAPK activity; ISS:UniProtKB.
DR   GO; GO:0032148; P:activation of protein kinase B activity; ISS:UniProtKB.
DR   GO; GO:0007171; P:activation of transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
DR   GO; GO:0038127; P:ERBB signaling pathway; ISS:UniProtKB.
DR   GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR   GO; GO:0007613; P:memory; IMP:RGD.
DR   GO; GO:2000853; P:negative regulation of corticosterone secretion; IMP:RGD.
DR   GO; GO:0007399; P:nervous system development; IBA:GO_Central.
DR   GO; GO:0048680; P:positive regulation of axon regeneration; IDA:RGD.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:RGD.
DR   GO; GO:0010976; P:positive regulation of neuron projection development; IDA:RGD.
DR   GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:RGD.
DR   GO; GO:0010625; P:positive regulation of Schwann cell proliferation; IMP:RGD.
DR   GO; GO:0032570; P:response to progesterone; IEP:RGD.
DR   Gene3D; 2.60.40.10; -; 1.
DR   InterPro; IPR013032; EGF-like_CS.
DR   InterPro; IPR000742; EGF-like_dom.
DR   InterPro; IPR007110; Ig-like_dom.
DR   InterPro; IPR036179; Ig-like_dom_sf.
DR   InterPro; IPR013783; Ig-like_fold.
DR   InterPro; IPR013098; Ig_I-set.
DR   InterPro; IPR003599; Ig_sub.
DR   InterPro; IPR003598; Ig_sub2.
DR   InterPro; IPR040180; Neuregulin.
DR   InterPro; IPR002154; Neuregulin_C.
DR   InterPro; IPR018250; NRG1.
DR   PANTHER; PTHR11100; PTHR11100; 1.
DR   PANTHER; PTHR11100:SF7; PTHR11100:SF7; 1.
DR   Pfam; PF07679; I-set; 1.
DR   Pfam; PF02158; Neuregulin; 1.
DR   PRINTS; PR01089; NEUREGULIN.
DR   SMART; SM00181; EGF; 1.
DR   SMART; SM00409; IG; 1.
DR   SMART; SM00408; IGc2; 1.
DR   SUPFAM; SSF48726; SSF48726; 1.
DR   PROSITE; PS00022; EGF_1; 1.
DR   PROSITE; PS50026; EGF_3; 1.
DR   PROSITE; PS50835; IG_LIKE; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cell membrane; Complete proteome;
KW   Direct protein sequencing; Disulfide bond; EGF-like domain;
KW   Glycoprotein; Growth factor; Immunoglobulin domain; Membrane;
KW   Reference proteome; Secreted; Transmembrane; Transmembrane helix.
FT   PROPEP        1     13       {ECO:0000269|PubMed:1348215}.
FT                                /FTId=PRO_0000019465.
FT   CHAIN        14    662       Pro-neuregulin-1, membrane-bound isoform.
FT                                /FTId=PRO_0000019466.
FT   CHAIN        14    264       Neuregulin-1.
FT                                /FTId=PRO_0000019467.
FT   TOPO_DOM     14    265       Extracellular. {ECO:0000255}.
FT   TRANSMEM    266    288       Helical; Note=Internal signal sequence.
FT                                {ECO:0000255}.
FT   TOPO_DOM    289    662       Cytoplasmic. {ECO:0000255}.
FT   DOMAIN       37    128       Ig-like C2-type.
FT   DOMAIN      178    222       EGF-like. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   COMPBIAS    165    177       Ser/Thr-rich.
FT   CARBOHYD    120    120       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    126    126       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    164    164       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   DISULFID     57    112
FT   DISULFID    182    196       {ECO:0000250}.
FT   DISULFID    190    210       {ECO:0000250}.
FT   DISULFID    212    221       {ECO:0000250}.
FT   VAR_SEQ     213    256       PNEFTGDRCQNYVMASFYMTSRRKRQETEKPLERKLDHSLV
FT                                KES -> QPGFTGARCTENVPMKVQTQE (in isoform
FT                                Alpha2A, isoform Alpha2B and isoform
FT                                Alpha2C). {ECO:0000303|PubMed:1349853}.
FT                                /FTId=VSP_003436.
FT   VAR_SEQ     231    257       MTSRRKRQETEKPLERKLDHSLVKESK -> KHLGIEFME
FT                                (in isoform Beta1). {ECO:0000305}.
FT                                /FTId=VSP_003437.
FT   VAR_SEQ     231    256       Missing (in isoform Beta2 and isoform
FT                                BetA2A). {ECO:0000305}.
FT                                /FTId=VSP_003440.
FT   VAR_SEQ     231    241       MTSRRKRQETE -> STSTPFLSLPE (in isoform
FT                                Beta3). {ECO:0000305}.
FT                                /FTId=VSP_003438.
FT   VAR_SEQ     242    662       Missing (in isoform Beta3).
FT                                {ECO:0000305}.
FT                                /FTId=VSP_003439.
FT   VAR_SEQ     325    330       PPENVQ -> RVRTRG (in isoform Beta2).
FT                                {ECO:0000305}.
FT                                /FTId=VSP_003441.
FT   VAR_SEQ     446    662       Missing (in isoform Alpha2C).
FT                                {ECO:0000303|PubMed:1349853}.
FT                                /FTId=VSP_003442.
FT   VAR_SEQ     446    484       YVSAMTTPARMSPVDFHTPSSPKSPPSEMSPPVSSMTVS
FT                                -> HNLIAELRRNKAYRSKCMQIQLSATHLRPSSITHLGFI
FT                                L (in isoform Alpha2B). {ECO:0000305}.
FT                                /FTId=VSP_003443.
FT   VAR_SEQ     485    662       Missing (in isoform Alpha2B).
FT                                {ECO:0000305}.
FT                                /FTId=VSP_003444.
FT   CONFLICT     90     90       K -> N (in Ref. 2; AA sequence).
FT                                {ECO:0000305}.
FT   CONFLICT    137    137       T -> I (in Ref. 2; AA sequence).
FT                                {ECO:0000305}.
FT   CONFLICT    208    208       Y -> S (in Ref. 2; AA sequence).
FT                                {ECO:0000305}.
SQ   SEQUENCE   662 AA;  73288 MW;  1C31ABCF2A8EB1D5 CRC64;
     MSERKEGRGK GKGKKKDRGS RGKPGPAEGD PSPALPPRLK EMKSQESAAG SKLVLRCETS
     SEYSSLRFKW FKNGNELNRK NKPENIKIQK KPGKSELRIN KASLADSGEY MCKVISKLGN
     DSASANITIV ESNEFITGMP ASTETAYVSS ESPIRISVST EGANTSSSTS TSTTGTSHLI
     KCAEKEKTFC VNGGECFTVK DLSNPSRYLC KCPNEFTGDR CQNYVMASFY MTSRRKRQET
     EKPLERKLDH SLVKESKAEE LYQKRVLTIT GICIALLVVG IMCVVAYCKT KKQRQKLHDR
     LRQSLRSERS NLVNIANGPH HPNPPPENVQ LVNQYVSKNV ISSEHIVERE VETSFSTSHY
     TSTAHHSTTV TQTPSHSWSN GHTESVISES NSVIMMSSVE NSRHSSPAGG PRGRLHGLGG
     PRDNSFLRHA RETPDSYRDS PHSERYVSAM TTPARMSPVD FHTPSSPKSP PSEMSPPVSS
     MTVSMPSVAV SPFVEEERPL LLVTPPRLRE KKYDHHPQQL NSFHHNPAHQ STSLPPSPLR
     IVEDEEYETT QEYESVQEPV KKVTNSRRAK RTKPNGHIAN RLEMDSNTSS VSSNSESETE
     DERVGEDTPF LGIQNPLAAS LEVAPAFRLA ESRTNPAGRF STQEELQARL SSVIANQDPI
     AV
//
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