NRG1_HUMAN
ID NRG1_HUMAN Reviewed; 640 AA.
AC Q02297; A5YAK4; A5YAK5; A8K1L2; B7Z4Z3; E9PHH4; O14667; P98202; Q02298;
AC Q02299; Q07110; Q07111; Q12779; Q12780; Q12781; Q12782; Q12783; Q12784;
AC Q15491; Q7RTV9; Q7RTW0; Q7RTW1; Q7RTW2; Q8NFN1; Q8NFN2; Q8NFN3; Q9UPE3;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 238.
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=Breast cancer cell differentiation factor p45;
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=GGF, HGL, HRGA, NDF, SMDF;
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] (ISOFORMS 1; 6; 7 AND 8), AND PARTIAL PROTEIN
RP SEQUENCE.
RX PubMed=1350381; DOI=10.1126/science.256.5060.1205;
RA Holmes W.E., Sliwkowski M.X., Akita R.W., Henzel W.J., Lee J., Park J.W.,
RA Yansura D., Abadi N., Raab H., Lewis G.D., Shepard H.M., Kuang W.-J.,
RA Wood W.I., Goeddel D.V., Vandlen R.L.;
RT "Identification of heregulin, a specific activator of p185erbB2.";
RL Science 256:1205-1210(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4; 6; 7 AND 8).
RC TISSUE=Kidney adenocarcinoma, and Pituitary;
RX PubMed=7509448; DOI=10.1128/mcb.14.3.1909-1919.1994;
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., Meng S.-Y.,
RA Lu H.S., Hu S., Chang D., Yang W., Yanigahara D., 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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 8 AND 9).
RC TISSUE=Brain;
RX PubMed=8096067; DOI=10.1038/362312a0;
RA Marchionni M.A., Goodearl A.D.J., Chen M.S., Bermingham-McDonogh O.,
RA Kirk C., Hendricks M., Danehy F., Misumi D., Sudhalter J., Kobayashi K.,
RA Wroblewski D., Lynch C., Baldasarre M., Hiles I., Davis J.B., Hsuan J.J.,
RA Totty N.F., Otsu M., McBurney R.N., Waterfield M.D., Stroobant P.,
RA Gwynne D.;
RT "Glial growth factors are alternatively spliced erbB2 ligands expressed in
RT the nervous system.";
RL Nature 362:312-318(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 10).
RC TISSUE=Brain stem, and Cerebellum;
RX PubMed=7782315; DOI=10.1074/jbc.270.24.14523;
RA Ho W.-H., Armanini M.P., Nuijens A., Phillips H.S., Osheroff P.L.;
RT "Sensory and motor neuron-derived factor. A novel heregulin variant highly
RT expressed in sensory and motor neurons.";
RL J. Biol. Chem. 270:14523-14532(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 10 AND 12), AND VARIANT
RP THR-289.
RC TISSUE=Hippocampus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [7]
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF GAMMA-HEREGULIN FUSION PROTEIN.
RC TISSUE=Mammary cancer;
RX PubMed=9333014; DOI=10.1038/sj.onc.1201317;
RA Schaefer G., Fitzpatrick V.D., Sliwkowski M.X.;
RT "Gamma-heregulin: a novel heregulin isoform that is an autocrine growth
RT factor for the human breast cancer cell line, MDA-MB-175.";
RL Oncogene 15:1385-1394(1997).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1; 3; 8 AND 9), AND
RP SUSCEPTIBILITY TO SCHIZOPHRENIA.
RX PubMed=12145742; DOI=10.1086/342734;
RA Stefansson H., Sigurdsson E., Steinthorsdottir V., Bjornsdottir S.,
RA Sigmundsson T., Ghosh S., Brynjolfsson J., Gunnarsdottir S., Ivarsson O.,
RA Chou T.T., Hjaltason O., Birgisdottir B., Jonsson H., Gudnadottir V.G.,
RA Gudmundsdottir E., Bjornsson A., Ingvarsson B., Ingason A., Sigfusson S.,
RA Hardardottir H., Harvey R.P., Brunner D., Mutel V., Gonzalo A., Lemke G.,
RA Sainz J., Johannesson G., Andresson T., Gudbjartsson D., Manolescu A.,
RA Frigge M.L., Gurney M.E., Kong A., Gulcher J.R., Petursson H.,
RA Stefansson K.;
RT "Neuregulin 1 and susceptibility to Schizophrenia.";
RL Am. J. Hum. Genet. 71:877-892(2002).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 11), ALTERNATIVE SPLICING, VARIANTS
RP GLN-38 AND THR-289, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC TISSUE=Hippocampus, and Prefrontal cortex;
RX PubMed=17565985; DOI=10.1074/jbc.m702953200;
RA Tan W., Wang Y., Gold B., Chen J., Dean M., Harrison P.J., Weinberger D.R.,
RA Law A.J.;
RT "Molecular cloning of a brain-specific, developmentally regulated
RT neuregulin 1 (NRG1) isoform and identification of a functional promoter
RT variant associated with schizophrenia.";
RL J. Biol. Chem. 282:24343-24351(2007).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 10).
RC TISSUE=Brain, and Duodenum;
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).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-211 (ISOFORM 1).
RA Schoumacher F., Herzer S., Flury N., Kueng W., Mueller H., Eppenberger U.;
RL Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP PROTEIN SEQUENCE OF 20-28.
RX PubMed=7689552; DOI=10.1016/s0021-9258(17)46636-1;
RA Culouscou J.-M., Plowman G.D., Carlton G.W., Green J.M., Shoyab M.;
RT "Characterization of a breast cancer cell differentiation factor that
RT specifically activates the HER4/p180erbB4 receptor.";
RL J. Biol. Chem. 268:18407-18410(1993).
RN [14]
RP PARTIAL PROTEIN SEQUENCE (ISOFORM 1), FUNCTION, AND GLYCOSYLATION.
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., Levy R.B.,
RA Yarden Y.;
RT "Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that
RT induces differentiation of mammary tumor cells.";
RL Cell 69:205-216(1992).
RN [15]
RP BINDING TO ERBB4, AND FUNCTION.
RX PubMed=7902537; DOI=10.1038/366473a0;
RA Plowman G.D., Green J.M., Culouscou J.M., Carlton G.W., Rothwell V.M.,
RA Buckley S.;
RT "Heregulin induces tyrosine phosphorylation of HER4/p180erbB4.";
RL Nature 366:473-475(1993).
RN [16]
RP CHROMOSOMAL TRANSLOCATION.
RX PubMed=10523851; DOI=10.1038/sj.onc.1202950;
RA Wang X.-Z., Jolicoeur E.M., Conte N., Chaffanet M., Zhang Y.,
RA Mozziconacci M.-J., Feiner H., Birnbaum D., Pebusque M.-J., Ron D.;
RT "Gamma-heregulin is the product of a chromosomal translocation fusing the
RT DOC4 and HGL/NRG1 genes in the MDA-MB-175 breast cancer cell line.";
RL Oncogene 18:5718-5721(1999).
RN [17]
RP CHROMOSOMAL TRANSLOCATION.
RX PubMed=10597312; DOI=10.1038/sj.onc.1203136;
RA Liu X., Baker E., Eyre H.J., Sutherland G.R., Zhou M.;
RT "Gamma-heregulin: a fusion gene of DOC-4 and neuregulin-1 derived from a
RT chromosome translocation.";
RL Oncogene 18:7110-7114(1999).
RN [18]
RP BINDING TO 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).
RN [19]
RP FUNCTION, BINDING TO ERBB3 AND INTEGRINS, IDENTIFICATION IN A TERNARY
RP COMPLEX WITH ERBB3 AND INTEGRINS, AND MUTAGENESIS OF LYS-181; LYS-185 AND
RP LYS-187.
RX PubMed=20682778; DOI=10.1074/jbc.m110.113878;
RA Ieguchi K., Fujita M., Ma Z., Davari P., Taniguchi Y., Sekiguchi K.,
RA Wang B., Takada Y.K., Takada Y.;
RT "Direct binding of the EGF-like domain of neuregulin-1 to integrins
RT ({alpha}v{beta}3 and {alpha}6{beta}4) is involved in neuregulin-1/ErbB
RT signaling.";
RL J. Biol. Chem. 285:31388-31398(2010).
RN [20]
RP STRUCTURE BY NMR OF 175-241 (ISOFORM 1).
RX PubMed=8062828; DOI=10.1002/j.1460-2075.1994.tb06658.x;
RA Nagata K., Kohda D., Hatanaka H., Ichikawa S., Matsuda S., Yamamoto T.,
RA Suzuki A., Inagaki F.;
RT "Solution structure of the epidermal growth factor-like domain of
RT heregulin-alpha, a ligand for p180erbB-4.";
RL EMBO J. 13:3517-3523(1994).
RN [21]
RP STRUCTURE BY NMR OF 177-239 (ISOFORM 1), AND DISULFIDE BONDS.
RX PubMed=8639490; DOI=10.1021/bi952626l;
RA Jacobsen N.E., Abadi N., Sliwkowski M.X., Reilly D., Skelton N.J.,
RA Fairbrother W.J.;
RT "High-resolution solution structure of the EGF-like domain of heregulin-
RT alpha.";
RL Biochemistry 35:3402-3417(1996).
CC -!- FUNCTION: Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors.
CC Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in
CC ligand-stimulated tyrosine phosphorylation and activation of the ERBB
CC receptors. The multiple isoforms perform diverse functions such as
CC inducing growth and differentiation of epithelial, glial, neuronal, and
CC skeletal muscle cells; inducing expression of acetylcholine receptor in
CC synaptic vesicles during the formation of the neuromuscular junction;
CC stimulating lobuloalveolar budding and milk production in the mammary
CC gland 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. Isoform 10
CC may play a role in motor and sensory neuron development. Binds to ERBB4
CC (PubMed:10867024, PubMed:7902537). Binds to ERBB3 (PubMed:20682778).
CC Acts as a ligand for integrins and binds (via EGF domain) to integrins
CC ITGAV:ITGB3 or ITGA6:ITGB4. Its binding to integrins and subsequent
CC ternary complex formation with integrins and ERRB3 are essential for
CC NRG1-ERBB signaling. Induces the phosphorylation and activation of
CC MAPK3/ERK1, MAPK1/ERK2 and AKT1 (PubMed:20682778). Ligand-dependent
CC ERBB4 endocytosis is essential for the NRG1-mediated activation of
CC these kinases in neurons (By similarity).
CC {ECO:0000250|UniProtKB:P43322, ECO:0000269|PubMed:10867024,
CC ECO:0000269|PubMed:1348215, ECO:0000269|PubMed:20682778,
CC ECO:0000269|PubMed:7902537}.
CC -!- SUBUNIT: The cytoplasmic domain interacts with the LIM domain region of
CC LIMK1 (By similarity). Forms a ternary complex with ERBB3 and
CC ITGAV:ITGB3 or ITGA6:ITGB4 (PubMed:20682778).
CC {ECO:0000250|UniProtKB:P43322, ECO:0000269|PubMed:20682778}.
CC -!- INTERACTION:
CC Q02297-6; P21860: ERBB3; NbExp=2; IntAct=EBI-15651799, EBI-720706;
CC Q02297-6; Q15303: ERBB4; NbExp=3; IntAct=EBI-15651799, EBI-80371;
CC Q02297-7; P04626: ERBB2; NbExp=2; IntAct=EBI-2460927, EBI-641062;
CC Q02297-7; P21860: ERBB3; NbExp=3; IntAct=EBI-2460927, EBI-720706;
CC Q02297-10; P07307-3: ASGR2; NbExp=3; IntAct=EBI-12842334, EBI-12808270;
CC Q02297-10; P21854: CD72; NbExp=3; IntAct=EBI-12842334, EBI-307924;
CC Q02297-10; Q8N5M9: JAGN1; NbExp=3; IntAct=EBI-12842334, EBI-10266796;
CC Q02297-10; Q86VI4: LAPTM4B; NbExp=3; IntAct=EBI-12842334, EBI-3267258;
CC Q02297-10; Q96JQ5: MS4A4A; NbExp=3; IntAct=EBI-12842334, EBI-12820341;
CC Q02297-10; P60201-2: PLP1; NbExp=3; IntAct=EBI-12842334, EBI-12188331;
CC Q02297-10; Q969K7: TMEM54; NbExp=3; IntAct=EBI-12842334, EBI-3922833;
CC -!- SUBCELLULAR LOCATION: [Pro-neuregulin-1, membrane-bound isoform]: Cell
CC membrane; Single-pass type I membrane protein. Note=Does not seem to be
CC active.
CC -!- SUBCELLULAR LOCATION: [Neuregulin-1]: Secreted.
CC -!- SUBCELLULAR LOCATION: [Isoform 8]: Nucleus. Note=May be nuclear.
CC -!- SUBCELLULAR LOCATION: [Isoform 9]: Secreted. Note=Has a signal peptide.
CC -!- SUBCELLULAR LOCATION: [Isoform 10]: Membrane; Single-pass type I
CC membrane protein. Note=May possess an internal uncleaved signal
CC sequence.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=11;
CC Comment=Additional isoforms seem to exist. Isoforms have been
CC classified as type I NRGs (isoforms with an Ig domain and a
CC glycosylation domain, isoforms 1-8), type II NRGs (isoforms with an
CC Ig domain but no glycosylation domain, isoform 9), type III NRGs
CC (isoforms with a Cys-rich domain, isoform 10) and type IV NRGs
CC (isoforms with additional 5' exons, isoform 11). All these isoforms
CC perform distinct tissue-specific functions.;
CC Name=1; Synonyms=Alpha;
CC IsoId=Q02297-1; Sequence=Displayed;
CC Name=2; Synonyms=Alpha1A;
CC IsoId=Q02297-2; Sequence=VSP_003431;
CC Name=3; Synonyms=Alpha2B;
CC IsoId=Q02297-3; Sequence=VSP_003434, VSP_003435;
CC Name=4; Synonyms=Alpha3;
CC IsoId=Q02297-4; Sequence=VSP_003432, VSP_003433;
CC Name=6; Synonyms=Beta1, Beta1A;
CC IsoId=Q02297-6; Sequence=VSP_003428;
CC Name=7; Synonyms=Beta2;
CC IsoId=Q02297-7; Sequence=VSP_003427;
CC Name=8; Synonyms=Beta3, GGFHFB1;
CC IsoId=Q02297-8; Sequence=VSP_003429, VSP_003430;
CC Name=9; Synonyms=GGF2, GGFHPP2;
CC IsoId=Q02297-9; Sequence=VSP_003425, VSP_003426, VSP_003429,
CC VSP_003430;
CC Name=10; Synonyms=SMDF;
CC IsoId=Q02297-10; Sequence=VSP_037562, VSP_037565, VSP_003429,
CC VSP_003430;
CC Name=11; Synonyms=Type IV-beta1a;
CC IsoId=Q02297-11; Sequence=VSP_037563, VSP_037564, VSP_003426,
CC VSP_003428;
CC Name=12;
CC IsoId=Q02297-12; Sequence=VSP_003427, VSP_046417;
CC -!- TISSUE SPECIFICITY: Type I isoforms are the predominant forms expressed
CC in the endocardium. Isoform alpha is expressed in breast, ovary,
CC testis, prostate, heart, skeletal muscle, lung, placenta liver, kidney,
CC salivary gland, small intestine and brain, but not in uterus, stomach,
CC pancreas, and spleen. Isoform 3 is the predominant form in mesenchymal
CC cells and in non-neuronal organs, whereas isoform 6 is the major
CC neuronal form. Isoform 8 is expressed in spinal cord and brain. Isoform
CC 9 is the major form in skeletal muscle cells; in the nervous system it
CC is expressed in spinal cord and brain. Also detected in adult heart,
CC placenta, lung, liver, kidney, and pancreas. Isoform 10 is expressed in
CC nervous system: spinal cord motor neurons, dorsal root ganglion
CC neurons, and brain. Predominant isoform expressed in sensory and motor
CC neurons. Not detected in adult heart, placenta, lung, liver, skeletal
CC muscle, kidney, and pancreas. Not expressed in fetal lung, liver and
CC kidney. Type IV isoforms are brain-specific.
CC {ECO:0000269|PubMed:17565985}.
CC -!- DEVELOPMENTAL STAGE: Detectable at early embryonic ages. Isoform 10 is
CC highly expressed in developing spinal motor neurons and in developing
CC cranial nerve nuclei. Expression is maintained only in both adult motor
CC neurons and dorsal root ganglion neurons. Type IV isoforms are
CC expressed in fetal brain. {ECO:0000269|PubMed:17565985}.
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.
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: N- and O-glycosylated. Extensive glycosylation precedes the
CC proteolytic cleavage (By similarity). {ECO:0000250}.
CC -!- DISEASE: Note=A chromosomal aberration involving NRG1 produces gamma-
CC heregulin. Translocation t(8;11) with TENM4. The translocation fuses
CC the 5'-end of TENM4 to NRG1 (isoform 8). The product of this
CC translocation was first thought to be an alternatively spliced isoform.
CC Gamma-heregulin is a soluble activating ligand for the ERBB2-ERBB3
CC receptor complex and acts as an autocrine growth factor in a specific
CC breast cancer cell line (MDA-MB-175). Not detected in breast carcinoma
CC samples, including ductal, lobular, medullary, and mucinous
CC histological types, neither in other breast cancer cell lines.
CC -!- MISCELLANEOUS: [Isoform 10]: Potential internal signal sequence at
CC positions 76-100. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the neuregulin family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA19955.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305};
CC Sequence=AAC51756.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Tipping the mind - Issue 129
CC of June 2011;
CC URL="https://web.expasy.org/spotlight/back_issues/129";
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DR EMBL; M94165; AAA58638.1; -; mRNA.
DR EMBL; M94166; AAA58639.1; -; mRNA.
DR EMBL; M94167; AAA58640.1; -; mRNA.
DR EMBL; M94168; AAA58641.1; -; mRNA.
DR EMBL; U02325; AAA19950.1; -; mRNA.
DR EMBL; U02326; AAA19951.1; -; mRNA.
DR EMBL; U02327; AAA19952.1; -; mRNA.
DR EMBL; U02328; AAA19953.1; -; mRNA.
DR EMBL; U02329; AAA19954.1; -; mRNA.
DR EMBL; U02330; AAA19955.1; ALT_SEQ; mRNA.
DR EMBL; L12260; AAB59622.1; -; mRNA.
DR EMBL; L12261; AAB59358.1; -; mRNA.
DR EMBL; L41827; AAC41764.1; -; mRNA.
DR EMBL; AK289927; BAF82616.1; -; mRNA.
DR EMBL; AK298132; BAH12729.1; -; mRNA.
DR EMBL; AC021909; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022833; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC022850; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC023948; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC068359; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC068931; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC083977; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC103675; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC104000; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC104029; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC113209; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF009227; AAC51756.1; ALT_INIT; mRNA.
DR EMBL; AF491780; AAM71137.1; -; Genomic_DNA.
DR EMBL; AF491780; AAM71139.1; -; Genomic_DNA.
DR EMBL; AF491780; AAM71140.1; -; Genomic_DNA.
DR EMBL; EF372273; ABQ53539.1; -; mRNA.
DR EMBL; EF372274; ABQ53540.1; -; mRNA.
DR EMBL; CH471080; EAW63411.1; -; Genomic_DNA.
DR EMBL; BC064587; AAH64587.1; -; mRNA.
DR EMBL; BC073871; AAH73871.1; -; mRNA.
DR EMBL; AF026146; AAD01795.1; -; mRNA.
DR EMBL; BK000383; DAA00044.1; -; Genomic_DNA.
DR EMBL; BK000383; DAA00045.1; -; Genomic_DNA.
DR EMBL; BK000383; DAA00046.1; -; Genomic_DNA.
DR EMBL; BK000383; DAA00047.1; -; Genomic_DNA.
DR CCDS; CCDS47836.1; -. [Q02297-9]
DR CCDS; CCDS55218.1; -. [Q02297-11]
DR CCDS; CCDS55219.1; -. [Q02297-12]
DR CCDS; CCDS6083.1; -. [Q02297-6]
DR CCDS; CCDS6084.1; -. [Q02297-7]
DR CCDS; CCDS6085.1; -. [Q02297-1]
DR CCDS; CCDS6086.1; -. [Q02297-3]
DR CCDS; CCDS6087.1; -. [Q02297-10]
DR PIR; A43273; A43273.
DR PIR; A56943; A56943.
DR PIR; B43273; B43273.
DR PIR; C43273; C43273.
DR PIR; D43273; D43273.
DR PIR; I38403; I38403.
DR PIR; I38404; I38404.
DR PIR; I38408; I38408.
DR PIR; S32357; S32357.
DR RefSeq; NP_001153467.1; NM_001159995.2.
DR RefSeq; NP_001153471.1; NM_001159999.2.
DR RefSeq; NP_001153473.1; NM_001160001.2. [Q02297-11]
DR RefSeq; NP_001153477.1; NM_001160005.1.
DR RefSeq; NP_001153480.1; NM_001160008.1. [Q02297-12]
DR RefSeq; NP_001309134.1; NM_001322205.1.
DR RefSeq; NP_001309135.1; NM_001322206.1.
DR RefSeq; NP_001309136.1; NM_001322207.1.
DR RefSeq; NP_039250.2; NM_013956.4. [Q02297-6]
DR RefSeq; NP_039251.2; NM_013957.4. [Q02297-7]
DR RefSeq; NP_039252.2; NM_013958.3. [Q02297-8]
DR RefSeq; NP_039253.1; NM_013959.3. [Q02297-10]
DR RefSeq; NP_039254.1; NM_013960.4. [Q02297-3]
DR RefSeq; NP_039256.2; NM_013962.2. [Q02297-9]
DR RefSeq; NP_039258.1; NM_013964.4. [Q02297-1]
DR PDB; 1HAE; NMR; -; A=177-239.
DR PDB; 1HAF; NMR; -; A=177-239.
DR PDB; 1HRE; NMR; -; A=175-241.
DR PDB; 1HRF; NMR; -; A=175-241.
DR PDB; 3U7U; X-ray; 3.03 A; G/H/I/J/K/L=175-212.
DR PDB; 7MN5; EM; 2.93 A; H=176-237.
DR PDB; 7MN6; EM; 3.09 A; H=176-237.
DR PDB; 7MN8; EM; 3.45 A; H=176-237.
DR PDBsum; 1HAE; -.
DR PDBsum; 1HAF; -.
DR PDBsum; 1HRE; -.
DR PDBsum; 1HRF; -.
DR PDBsum; 3U7U; -.
DR PDBsum; 7MN5; -.
DR PDBsum; 7MN6; -.
DR PDBsum; 7MN8; -.
DR AlphaFoldDB; Q02297; -.
DR SMR; Q02297; -.
DR BioGRID; 109332; 106.
DR CORUM; Q02297; -.
DR DIP; DIP-355N; -.
DR IntAct; Q02297; 56.
DR MINT; Q02297; -.
DR STRING; 9606.ENSP00000384620; -.
DR GlyGen; Q02297; 3 sites.
DR iPTMnet; Q02297; -.
DR PhosphoSitePlus; Q02297; -.
DR BioMuta; NRG1; -.
DR DMDM; 9297018; -.
DR jPOST; Q02297; -.
DR MassIVE; Q02297; -.
DR MaxQB; Q02297; -.
DR PaxDb; Q02297; -.
DR PeptideAtlas; Q02297; -.
DR PRIDE; Q02297; -.
DR ProteomicsDB; 20533; -.
DR ProteomicsDB; 58070; -. [Q02297-1]
DR ProteomicsDB; 58071; -. [Q02297-10]
DR ProteomicsDB; 58072; -. [Q02297-11]
DR ProteomicsDB; 58073; -. [Q02297-2]
DR ProteomicsDB; 58074; -. [Q02297-3]
DR ProteomicsDB; 58075; -. [Q02297-4]
DR ProteomicsDB; 58076; -. [Q02297-6]
DR ProteomicsDB; 58077; -. [Q02297-7]
DR ProteomicsDB; 58078; -. [Q02297-8]
DR ProteomicsDB; 58079; -. [Q02297-9]
DR ABCD; Q02297; 1 sequenced antibody.
DR Antibodypedia; 3706; 989 antibodies from 45 providers.
DR DNASU; 3084; -.
DR Ensembl; ENST00000287842.7; ENSP00000287842.4; ENSG00000157168.20. [Q02297-6]
DR Ensembl; ENST00000356819.7; ENSP00000349275.6; ENSG00000157168.20. [Q02297-7]
DR Ensembl; ENST00000405005.7; ENSP00000384620.2; ENSG00000157168.20. [Q02297-1]
DR Ensembl; ENST00000519301.6; ENSP00000429582.1; ENSG00000157168.20. [Q02297-11]
DR Ensembl; ENST00000520407.5; ENSP00000434640.1; ENSG00000157168.20. [Q02297-9]
DR Ensembl; ENST00000520502.7; ENSP00000433289.1; ENSG00000157168.20. [Q02297-10]
DR Ensembl; ENST00000521670.5; ENSP00000428828.1; ENSG00000157168.20. [Q02297-3]
DR Ensembl; ENST00000523079.5; ENSP00000430120.1; ENSG00000157168.20. [Q02297-12]
DR Ensembl; ENST00000650919.1; ENSP00000498811.1; ENSG00000157168.20. [Q02297-8]
DR GeneID; 3084; -.
DR KEGG; hsa:3084; -.
DR MANE-Select; ENST00000405005.8; ENSP00000384620.2; NM_013964.5; NP_039258.1.
DR UCSC; uc003xip.4; human. [Q02297-1]
DR CTD; 3084; -.
DR DisGeNET; 3084; -.
DR GeneCards; NRG1; -.
DR HGNC; HGNC:7997; NRG1.
DR HPA; ENSG00000157168; Tissue enhanced (brain).
DR MalaCards; NRG1; -.
DR MIM; 142445; gene.
DR neXtProt; NX_Q02297; -.
DR OpenTargets; ENSG00000157168; -.
DR PharmGKB; PA31776; -.
DR VEuPathDB; HostDB:ENSG00000157168; -.
DR eggNOG; ENOG502QRUM; Eukaryota.
DR GeneTree; ENSGT00940000157326; -.
DR HOGENOM; CLU_023628_1_0_1; -.
DR InParanoid; Q02297; -.
DR OMA; NQEKHLG; -.
DR OrthoDB; 313400at2759; -.
DR PhylomeDB; Q02297; -.
DR TreeFam; TF332469; -.
DR PathwayCommons; Q02297; -.
DR Reactome; R-HSA-1227986; Signaling by ERBB2. [Q02297-10]
DR Reactome; R-HSA-1236394; Signaling by ERBB4. [Q02297-10]
DR Reactome; R-HSA-1250196; SHC1 events in ERBB2 signaling. [Q02297-10]
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. [Q02297-10]
DR Reactome; R-HSA-1306955; GRB7 events in ERBB2 signaling. [Q02297-10]
DR Reactome; R-HSA-1358803; Downregulation of ERBB2:ERBB3 signaling. [Q02297-10]
DR Reactome; R-HSA-1963640; GRB2 events in ERBB2 signaling.
DR Reactome; R-HSA-1963642; PI3K events in ERBB2 signaling. [Q02297-10]
DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer. [Q02297-10]
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade. [Q02297-10]
DR Reactome; R-HSA-6785631; ERBB2 Regulates Cell Motility. [Q02297-10]
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. [Q02297-10]
DR Reactome; R-HSA-8847993; ERBB2 Activates PTK6 Signaling. [Q02297-10]
DR Reactome; R-HSA-8863795; Downregulation of ERBB2 signaling. [Q02297-10]
DR Reactome; R-HSA-9620244; Long-term potentiation.
DR Reactome; R-HSA-9664565; Signaling by ERBB2 KD Mutants. [Q02297-10]
DR Reactome; R-HSA-9665686; Signaling by ERBB2 TMD/JMD mutants. [Q02297-10]
DR SignaLink; Q02297; -.
DR SIGNOR; Q02297; -.
DR BioGRID-ORCS; 3084; 10 hits in 1082 CRISPR screens.
DR ChiTaRS; NRG1; human.
DR EvolutionaryTrace; Q02297; -.
DR GeneWiki; Neuregulin_1; -.
DR GenomeRNAi; 3084; -.
DR Pharos; Q02297; Tbio.
DR PRO; PR:Q02297; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q02297; protein.
DR Bgee; ENSG00000157168; Expressed in ventricular zone and 140 other tissues.
DR ExpressionAtlas; Q02297; baseline and differential.
DR Genevisible; Q02297; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:BHF-UCL.
DR GO; GO:0030424; C:axon; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0098982; C:GABA-ergic synapse; IEA:Ensembl.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:Ensembl.
DR GO; GO:0099061; C:integral component of postsynaptic density membrane; IDA:SynGO.
DR GO; GO:0099059; C:integral component of presynaptic active zone membrane; IDA:SynGO.
DR GO; GO:0016020; C:membrane; NAS:UniProtKB.
DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0045499; F:chemorepellent activity; IBA:GO_Central.
DR GO; GO:0005125; F:cytokine activity; TAS:BHF-UCL.
DR GO; GO:0005176; F:ErbB-2 class receptor binding; IEA:Ensembl.
DR GO; GO:0043125; F:ErbB-3 class receptor binding; IDA:BHF-UCL.
DR GO; GO:0008083; F:growth factor activity; IDA:BHF-UCL.
DR GO; GO:0005178; F:integrin binding; IDA:UniProtKB.
DR GO; GO:0030296; F:protein tyrosine kinase activator activity; IDA:BHF-UCL.
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; IPI:BHF-UCL.
DR GO; GO:0003712; F:transcription coregulator activity; IDA:MGI.
DR GO; GO:0030297; F:transmembrane receptor protein tyrosine kinase activator activity; NAS:UniProtKB.
DR GO; GO:0032148; P:activation of protein kinase B activity; IMP:UniProtKB.
DR GO; GO:0007171; P:activation of transmembrane receptor protein tyrosine kinase activity; IDA:BHF-UCL.
DR GO; GO:0048513; P:animal organ development; IBA:GO_Central.
DR GO; GO:0003161; P:cardiac conduction system development; IEA:Ensembl.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; ISS:BHF-UCL.
DR GO; GO:0060379; P:cardiac muscle cell myoblast differentiation; IDA:BHF-UCL.
DR GO; GO:0007154; P:cell communication; TAS:BHF-UCL.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0000902; P:cell morphogenesis; IEA:Ensembl.
DR GO; GO:0008283; P:cell population proliferation; IDA:BHF-UCL.
DR GO; GO:0021842; P:chemorepulsion involved in interneuron migration from the subpallium to the cortex; IEA:Ensembl.
DR GO; GO:0060956; P:endocardial cell differentiation; IDA:BHF-UCL.
DR GO; GO:0038127; P:ERBB signaling pathway; IDA:BHF-UCL.
DR GO; GO:0038133; P:ERBB2-ERBB3 signaling pathway; IDA:MGI.
DR GO; GO:0038135; P:ERBB2-ERBB4 signaling pathway; IDA:MGI.
DR GO; GO:0038129; P:ERBB3 signaling pathway; IDA:CAFA.
DR GO; GO:0038130; P:ERBB4 signaling pathway; IDA:UniProtKB.
DR GO; GO:0038138; P:ERBB4-ERBB4 signaling pathway; IDA:MGI.
DR GO; GO:0021781; P:glial cell fate commitment; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0007626; P:locomotory behavior; IEA:Ensembl.
DR GO; GO:0030879; P:mammary gland development; TAS:BHF-UCL.
DR GO; GO:0000165; P:MAPK cascade; IEA:Ensembl.
DR GO; GO:0022011; P:myelination in peripheral nervous system; IEA:Ensembl.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IDA:BHF-UCL.
DR GO; GO:2001223; P:negative regulation of neuron migration; IEA:Ensembl.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IEA:Ensembl.
DR GO; GO:0051048; P:negative regulation of secretion; IDA:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0007399; P:nervous system development; IBA:GO_Central.
DR GO; GO:0014032; P:neural crest cell development; TAS:BHF-UCL.
DR GO; GO:0048663; P:neuron fate commitment; IEA:Ensembl.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:0045213; P:neurotransmitter receptor metabolic process; IEA:Ensembl.
DR GO; GO:0048709; P:oligodendrocyte differentiation; IEA:Ensembl.
DR GO; GO:0070886; P:positive regulation of calcineurin-NFAT signaling cascade; IEA:Ensembl.
DR GO; GO:0060045; P:positive regulation of cardiac muscle cell proliferation; IDA:BHF-UCL.
DR GO; GO:0045785; P:positive regulation of cell adhesion; IDA:BHF-UCL.
DR GO; GO:0030307; P:positive regulation of cell growth; IDA:BHF-UCL.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:1900086; P:positive regulation of peptidyl-tyrosine autophosphorylation; IDA:UniProtKB.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IEA:Ensembl.
DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL.
DR GO; GO:0046579; P:positive regulation of Ras protein signal transduction; IEA:Ensembl.
DR GO; GO:0051155; P:positive regulation of striated muscle cell differentiation; ISS:BHF-UCL.
DR GO; GO:0099527; P:postsynapse to nucleus signaling pathway; IEA:Ensembl.
DR GO; GO:0030163; P:protein catabolic process; IEA:Ensembl.
DR GO; GO:0043491; P:protein kinase B signaling; IEA:Ensembl.
DR GO; GO:0032984; P:protein-containing complex disassembly; IGI:MGI.
DR GO; GO:0099149; P:regulation of postsynaptic neurotransmitter receptor internalization; IDA:SynGO.
DR GO; GO:0007416; P:synapse assembly; IEA:Ensembl.
DR GO; GO:0099560; P:synaptic membrane adhesion; IDA:SynGO.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IDA:BHF-UCL.
DR GO; GO:0055012; P:ventricular cardiac muscle cell differentiation; IDA:BHF-UCL.
DR GO; GO:0003222; P:ventricular trabecula myocardium morphogenesis; IDA:BHF-UCL.
DR GO; GO:0042060; P:wound healing; IDA:BHF-UCL.
DR DisProt; DP01520; -. [Q02297-10]
DR Gene3D; 2.60.40.10; -; 1.
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:SF25; PTHR11100:SF25; 1.
DR Pfam; PF00008; EGF; 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; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane;
KW Chromosomal rearrangement; Direct protein sequencing; Disulfide bond;
KW EGF-like domain; Glycoprotein; Growth factor; Immunoglobulin domain;
KW Membrane; Nucleus; Reference proteome; Secreted; Transmembrane;
KW Transmembrane helix.
FT PROPEP 1..19
FT /evidence="ECO:0000269|PubMed:7689552"
FT /id="PRO_0000019462"
FT CHAIN 20..640
FT /note="Pro-neuregulin-1, membrane-bound isoform"
FT /id="PRO_0000019463"
FT CHAIN 20..241
FT /note="Neuregulin-1"
FT /id="PRO_0000019464"
FT TOPO_DOM 20..242
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 243..265
FT /note="Helical; Note=Internal signal sequence"
FT /evidence="ECO:0000255"
FT TOPO_DOM 266..640
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 37..128
FT /note="Ig-like C2-type"
FT DOMAIN 178..222
FT /note="EGF-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT REGION 1..53
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 334..360
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 375..399
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 433..461
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 524..588
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 375..389
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 559..573
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 34
FT /note="Breakpoint for translocation to form gamma-
FT heregulin"
FT CARBOHYD 120
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 126
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 164
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 57..112
FT /evidence="ECO:0000250"
FT DISULFID 182..196
FT /evidence="ECO:0000269|PubMed:8639490"
FT DISULFID 190..210
FT /evidence="ECO:0000269|PubMed:8639490"
FT DISULFID 212..221
FT /evidence="ECO:0000269|PubMed:8639490"
FT VAR_SEQ 1..166
FT /note="Missing (in isoform 10)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:7782315"
FT /id="VSP_037562"
FT VAR_SEQ 1..33
FT /note="MSERKEGRGKGKGKKKERGSGKKPESAAGSQSP -> MRWRRAPRRSGRPGP
FT RAQRPGSAARSSPPLPLLPLLLLLGTAALAPGAAAGNEAAPAGASVCYSSPPSVGSVQE
FT LAQRAAVVIEGKVHPQRRQQGALDRKAAAAAGEAGAWGGDREPPAAGPRALGPPAEEPL
FT LAANGTVPSWPTAPVPSAGEPGEEAPYLVKVHQVWAVKAGGLKKDSLLTVRLGTWGHPA
FT FPSCGRLKEDSRYIFFMEPDANSTSRAPAAFRASFPPLETGRNLKKEVSRVLCKRC
FT (in isoform 9)"
FT /evidence="ECO:0000303|PubMed:8096067"
FT /id="VSP_003425"
FT VAR_SEQ 1..21
FT /note="Missing (in isoform 11)"
FT /evidence="ECO:0000303|PubMed:17565985"
FT /id="VSP_037563"
FT VAR_SEQ 22..33
FT /note="KKPESAAGSQSP -> MGKGRAGRVGTT (in isoform 11)"
FT /evidence="ECO:0000303|PubMed:17565985"
FT /id="VSP_037564"
FT VAR_SEQ 134..168
FT /note="EIITGMPASTEGAYVSSESPIRISVSTEGANTSSS -> A (in isoform
FT 9 and isoform 11)"
FT /evidence="ECO:0000303|PubMed:17565985,
FT ECO:0000303|PubMed:8096067"
FT /id="VSP_003426"
FT VAR_SEQ 167
FT /note="S -> MEIYSPDMSEVAAERSSSPSTQLSADPSLDGLPAAEDMPEPQTEDGR
FT TPGLVGLAVPCCACLEAERLRGCLNSEKICIVPILACLVSLCLCIAGLKWVFVDKIFEY
FT DSPTHLDPGGLGQDPIISLDATAASAVWVSSEAYTSPVSRAQSESEVQVTVQGDKAVVS
FT FEPSAAPTPKNRIFAFSFLPSTAPSFPSPTRNPEVRTPKSATQPQTTETNLQTAPKL
FT (in isoform 10)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:7782315"
FT /id="VSP_037565"
FT VAR_SEQ 213..241
FT /note="QPGFTGARCTENVPMKVQNQEKAEELYQK -> PNEFTGDRCQNYVMASFYS
FT TSTPFLSLPE (in isoform 8, isoform 9 and isoform 10)"
FT /evidence="ECO:0000303|PubMed:1350381,
FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:7509448, ECO:0000303|PubMed:7782315,
FT ECO:0000303|PubMed:8096067"
FT /id="VSP_003429"
FT VAR_SEQ 213..234
FT /note="QPGFTGARCTENVPMKVQNQEK -> PNEFTGDRCQNYVMASFYKHLGIEFM
FT E (in isoform 6 and isoform 11)"
FT /evidence="ECO:0000303|PubMed:1350381,
FT ECO:0000303|PubMed:17565985, ECO:0000303|PubMed:7509448"
FT /id="VSP_003428"
FT VAR_SEQ 213..233
FT /note="QPGFTGARCTENVPMKVQNQE -> PNEFTGDRCQNYVMASFY (in
FT isoform 7 and isoform 12)"
FT /evidence="ECO:0000303|PubMed:1350381,
FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:7509448"
FT /id="VSP_003427"
FT VAR_SEQ 234..247
FT /note="KAEELYQKRVLTIT -> SAQMSLLVIAAKTT (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:7509448"
FT /id="VSP_003432"
FT VAR_SEQ 234
FT /note="K -> KHLGIEFIE (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:7509448"
FT /id="VSP_003431"
FT VAR_SEQ 242..640
FT /note="Missing (in isoform 8, isoform 9 and isoform 10)"
FT /evidence="ECO:0000303|PubMed:1350381,
FT ECO:0000303|PubMed:14702039, ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:7509448, ECO:0000303|PubMed:7782315,
FT ECO:0000303|PubMed:8096067"
FT /id="VSP_003430"
FT VAR_SEQ 248..640
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:7509448"
FT /id="VSP_003433"
FT VAR_SEQ 424..640
FT /note="Missing (in isoform 12)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046417"
FT VAR_SEQ 424..462
FT /note="YVSAMTTPARMSPVDFHTPSSPKSPPSEMSPPVSSMTVS -> HNLIAELRR
FT NKAHRSKCMQIQLSATHLRSSSIPHLGFIL (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:7509448"
FT /id="VSP_003434"
FT VAR_SEQ 463..640
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:7509448"
FT /id="VSP_003435"
FT VARIANT 38
FT /note="R -> Q (in dbSNP:rs3924999)"
FT /evidence="ECO:0000269|PubMed:17565985"
FT /id="VAR_009307"
FT VARIANT 289
FT /note="M -> T (in dbSNP:rs10503929)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:17565985"
FT /id="VAR_053531"
FT VARIANT 463
FT /note="M -> K"
FT /id="VAR_009308"
FT MUTAGEN 181
FT /note="K->E: Defective in integrin-binding and in inducing
FT ERBB3 phosphorylation; when associated with or without E-
FT 185 or E-187. No effect on ERBB3-binding, defective in
FT integrin-binding and in ternary complex formation with
FT ERBB3 and integrins, and defective in inducing NRG1-ERBB
FT signaling; when associated with E-185 and E-187."
FT /evidence="ECO:0000269|PubMed:20682778"
FT MUTAGEN 185
FT /note="K->E: Defective in integrin-binding and in inducing
FT ERBB3 phosphorylation; when associated with or without E-
FT 181 or E-187. No effect on ERBB3-binding, defective in
FT integrin-binding and in ternary complex formation with
FT ERBB3 and integrins, and defective in inducing NRG1-ERBB
FT signaling; when associated with E-181 and E-187."
FT /evidence="ECO:0000269|PubMed:20682778"
FT MUTAGEN 187
FT /note="K->E: Defective in integrin-binding and in inducing
FT ERBB3 phosphorylation; when associated with or without E-
FT 181 or E-185. No effect on ERBB3-binding, defective in
FT integrin-binding and in ternary complex formation with
FT ERBB3 and integrins, and defective in inducing NRG1-ERBB
FT signaling; when associated with E-181 and E-185."
FT /evidence="ECO:0000269|PubMed:20682778"
FT CONFLICT 94
FT /note="K -> A (in Ref. 2; AAA19953)"
FT /evidence="ECO:0000305"
FT CONFLICT 107
FT /note="S -> P (in Ref. 10; ABQ53539)"
FT /evidence="ECO:0000305"
FT CONFLICT 261
FT /note="V -> L (in Ref. 10; ABQ53540)"
FT /evidence="ECO:0000305"
FT CONFLICT 414
FT /note="S -> F (in Ref. 2; AAA19953)"
FT /evidence="ECO:0000305"
FT CONFLICT 535
FT /note="Q -> R (in Ref. 2; AAA19951)"
FT /evidence="ECO:0000305"
FT STRAND 179..181
FT /evidence="ECO:0007829|PDB:7MN5"
FT TURN 184..186
FT /evidence="ECO:0007829|PDB:7MN5"
FT HELIX 187..189
FT /evidence="ECO:0007829|PDB:7MN5"
FT STRAND 190..193
FT /evidence="ECO:0007829|PDB:1HRE"
FT STRAND 196..199
FT /evidence="ECO:0007829|PDB:7MN5"
FT STRAND 200..204
FT /evidence="ECO:0007829|PDB:1HRE"
FT STRAND 208..212
FT /evidence="ECO:0007829|PDB:7MN5"
FT STRAND 216..218
FT /evidence="ECO:0007829|PDB:7MN5"
FT STRAND 233..235
FT /evidence="ECO:0007829|PDB:1HAF"
FT VARIANT Q02297-10:46
FT /note="G -> R (in dbSNP:rs3735774)"
FT /evidence="ECO:0000305"
FT /id="VAR_082866"
FT VARIANT Q02297-10:127
FT /note="A -> P (in dbSNP:rs34822181)"
FT /evidence="ECO:0000305"
FT /id="VAR_082867"
SQ SEQUENCE 640 AA; 70392 MW; C30D3F614AADFF62 CRC64;
MSERKEGRGK GKGKKKERGS GKKPESAAGS QSPALPPRLK EMKSQESAAG SKLVLRCETS
SEYSSLRFKW FKNGNELNRK NKPQNIKIQK KPGKSELRIN KASLADSGEY MCKVISKLGN
DSASANITIV ESNEIITGMP ASTEGAYVSS ESPIRISVST EGANTSSSTS TSTTGTSHLV
KCAEKEKTFC VNGGECFMVK DLSNPSRYLC KCQPGFTGAR CTENVPMKVQ NQEKAEELYQ
KRVLTITGIC IALLVVGIMC VVAYCKTKKQ RKKLHDRLRQ SLRSERNNMM NIANGPHHPN
PPPENVQLVN QYVSKNVISS EHIVEREAET SFSTSHYTST AHHSTTVTQT PSHSWSNGHT
ESILSESHSV IVMSSVENSR HSSPTGGPRG RLNGTGGPRE CNSFLRHARE TPDSYRDSPH
SERYVSAMTT PARMSPVDFH TPSSPKSPPS EMSPPVSSMT VSMPSMAVSP FMEEERPLLL
VTPPRLREKK FDHHPQQFSS FHHNPAHDSN SLPASPLRIV EDEEYETTQE YEPAQEPVKK
LANSRRAKRT KPNGHIANRL EVDSNTSSQS SNSESETEDE RVGEDTPFLG IQNPLAASLE
ATPAFRLADS RTNPAGRFST QEEIQARLSS VIANQDPIAV
