ERBB4_HUMAN
ID ERBB4_HUMAN Reviewed; 1308 AA.
AC Q15303; B7ZLD7; B7ZLE2; B7ZLE3; Q2M1W1; Q59EW4;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 234.
DE RecName: Full=Receptor tyrosine-protein kinase erbB-4;
DE EC=2.7.10.1;
DE AltName: Full=Proto-oncogene-like protein c-ErbB-4;
DE AltName: Full=Tyrosine kinase-type cell surface receptor HER4;
DE AltName: Full=p180erbB4;
DE Contains:
DE RecName: Full=ERBB4 intracellular domain;
DE Short=4ICD;
DE Short=E4ICD;
DE AltName: Full=s80HER4;
DE Flags: Precursor;
GN Name=ERBB4; Synonyms=HER4;
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 JM-A CYT-1), FUNCTION AS CELL SURFACE
RP RECEPTOR, AUTOPHOSPHORYLATION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Mammary carcinoma;
RX PubMed=8383326; DOI=10.1073/pnas.90.5.1746;
RA Plowman G.D., Culouscou J.-M., Whitney G.S., Green J.M., Carlton G.W.,
RA Foy L., Neubauer M.G., Shoyab M.;
RT "Ligand-specific activation of HER4/p180erbB4, a fourth member of the
RT epidermal growth factor receptor family.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:1746-1750(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS JM-A CYT-1 AND JM-B CYT-1), TISSUE
RP SPECIFICITY, FUNCTION AS CELL SURFACE RECEPTOR FOR NRG1 AND BTC,
RP SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, AND PROTEOLYTIC PROCESSING.
RC TISSUE=Fetal brain;
RX PubMed=9334263; DOI=10.1074/jbc.272.42.26761;
RA Elenius K., Corfas G., Paul S., Choi C.J., Rio C., Plowman G.D.,
RA Klagsbrun M.;
RT "A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific
RT tissue distribution and differential processing in response to phorbol
RT ester.";
RL J. Biol. Chem. 272:26761-26768(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS JM-A CYT-1; JM-B CYT-1;
RP JM-A CYT-2 AND JM-B CYT-2).
RC TISSUE=Brain;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 401-1308 (ISOFORM JM-A CYT-2).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP INTERACTION WITH NRG1, AND AUTOPHOSPHORYLATION.
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 [6]
RP INTERACTION WITH NRG1, AND AUTOPHOSPHORYLATION.
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 [7]
RP FUNCTION AS NRG1 RECEPTOR IN REGULATION OF CELL PROLIFERATION, CATALYTIC
RP ACTIVITY, ACTIVITY REGULATION, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT
RP TYR-1056; TYR-1188 AND TYR-1242, AND INTERACTION WITH EGFR; SHC1 AND
RP PIK3R1.
RX PubMed=8617750; DOI=10.1074/jbc.271.9.4813;
RA Cohen B.D., Green J.M., Foy L., Fell H.P.;
RT "HER4-mediated biological and biochemical properties in NIH 3T3 cells.
RT Evidence for HER1-HER4 heterodimers.";
RL J. Biol. Chem. 271:4813-4818(1996).
RN [8]
RP INTERACTION WITH BTC, AND AUTOPHOSPHORYLATION.
RX PubMed=8570211;
RA Riese D.J. II, Bermingham Y., van Raaij T.M., Buckley S., Plowman G.D.,
RA Stern D.F.;
RT "Betacellulin activates the epidermal growth factor receptor and erbB-4,
RT and induces cellular response patterns distinct from those stimulated by
RT epidermal growth factor or neuregulin-beta.";
RL Oncogene 12:345-353(1996).
RN [9]
RP FUNCTION AS HBEGF RECEPTOR; IN CELL MIGRATION; CELL PROLIFERATION AND IN
RP ACTIVATION OF PIK3R1, INTERACTION WITH HBEGF AND PIK3R1, AND
RP AUTOPHOSPHORYLATION.
RX PubMed=9135143; DOI=10.1093/emboj/16.6.1268;
RA Elenius K., Paul S., Allison G., Sun J., Klagsbrun M.;
RT "Activation of HER4 by heparin-binding EGF-like growth factor stimulates
RT chemotaxis but not proliferation.";
RL EMBO J. 16:1268-1278(1997).
RN [10]
RP INTERACTION WITH NRG2, FUNCTION AS NRG2 RECEPTOR, AND PHOSPHORYLATION.
RX PubMed=9168115; DOI=10.1038/387512a0;
RA Carraway K.L. III, Weber J.L., Unger M.J., Ledesma J., Yu N., Gassmann M.,
RA Lai C.;
RT "Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases.";
RL Nature 387:512-516(1997).
RN [11]
RP INTERACTION WITH EREG, AND AUTOPHOSPHORYLATION.
RX PubMed=9419975; DOI=10.1038/sj.onc.1201458;
RA Komurasaki T., Toyoda H., Uchida D., Morimoto S.;
RT "Epiregulin binds to epidermal growth factor receptor and ErbB-4 and
RT induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-
RT 2, ErbB-3 and ErbB-4.";
RL Oncogene 15:2841-2848(1997).
RN [12]
RP INTERACTION WITH NRG3, AND AUTOPHOSPHORYLATION.
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 [13]
RP INTERACTION WITH GRB7.
RX PubMed=9516479; DOI=10.1074/jbc.273.13.7717;
RA Fiddes R.J., Campbell D.H., Janes P.W., Sivertsen S.P., Sasaki H.,
RA Wallasch C., Daly R.J.;
RT "Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals
RT a novel target selectivity for erbB3.";
RL J. Biol. Chem. 273:7717-7724(1998).
RN [14]
RP INTERACTION WITH ERBB2, AND FUNCTION IN ACTIVATION OF STAT5A.
RX PubMed=10358079; DOI=10.1074/jbc.274.24.17209;
RA Olayioye M.A., Beuvink I., Horsch K., Daly J.M., Hynes N.E.;
RT "ErbB receptor-induced activation of stat transcription factors is mediated
RT by Src tyrosine kinases.";
RL J. Biol. Chem. 274:17209-17218(1999).
RN [15]
RP ALTERNATIVE SPLICING, FUNCTION IN PHOSPHORYLATION AND ACTIVATION OF PIK3R1,
RP INTERACTION WITH NRG1 AND PIKR3R1, AUTOPHOSPHORYLATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=10353604; DOI=10.1038/sj.onc.1202612;
RA Elenius K., Choi C.J., Paul S., Santiestevan E., Nishi E., Klagsbrun M.;
RT "Characterization of a naturally occurring ErbB4 isoform that does not bind
RT or activate phosphatidyl inositol 3-kinase.";
RL Oncogene 18:2607-2615(1999).
RN [16]
RP FUNCTION AS NRG4 RECEPTOR IN ACTIVATION OF MAPK1/ERK2 AND MAPK3/ERK1 AND IN
RP CELL PROLIFERATION, INTERACTION WITH NRG4, AND SUBCELLULAR LOCATION.
RX PubMed=10348342; DOI=10.1038/sj.onc.1202631;
RA Harari D., Tzahar E., Romano J., Shelly M., Pierce J.H., Andrews G.C.,
RA Yarden Y.;
RT "Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor
RT tyrosine kinase.";
RL Oncogene 18:2681-2689(1999).
RN [17]
RP FUNCTION AS NRG1 RECEPTOR IN CELL PROLIFERATION; MIGRATION; SURVIVAL AND IN
RP PHOSPHORYLATION OF SHC1; ACTIVATION OF MAPK1/ERK2 AND MAPK3/ERK1, AND
RP ALTERNATIVE SPLICING.
RX PubMed=10722704; DOI=10.1074/jbc.275.12.8641;
RA Kainulainen V., Sundvall M., Maatta J.A., Santiestevan E., Klagsbrun M.,
RA Elenius K.;
RT "A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase
RT mediates proliferation but not survival or chemotaxis.";
RL J. Biol. Chem. 275:8641-8649(2000).
RN [18]
RP PROTEOLYTIC PROCESSING.
RX PubMed=10744726; DOI=10.1074/jbc.275.14.10379;
RA Rio C., Buxbaum J.D., Peschon J.J., Corfas G.;
RT "Tumor necrosis factor-alpha-converting enzyme is required for cleavage of
RT erbB4/HER4.";
RL J. Biol. Chem. 275:10379-10387(2000).
RN [19]
RP FUNCTION IN ACTIVATION OF AKT1; MAPK1/ERK2 AND MAPK3/ERK1, INTERACTION WITH
RP PIK3R1; GRB2; SHC1; BTC; NRG1; NRG2 AND NRG3, AND LIGAND-SPECIFIC
RP AUTOPHOSPHORYLATION.
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 [20]
RP INTERACTION WITH DLG2; DLG3; DLG4 AND SNTB2.
RX PubMed=10725395; DOI=10.1073/pnas.97.7.3596;
RA Garcia R.A., Vasudevan K., Buonanno A.;
RT "The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at
RT neuronal synapses.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:3596-3601(2000).
RN [21]
RP FUNCTION AS NRG1 RECEPTOR AND IN ACTIVATION OF MAP KINASES,
RP AUTOPHOSPHORYLATION, AND ACTIVITY REGULATION.
RX PubMed=11178955; DOI=10.1006/bbrc.2001.4302;
RA Egeblad M., Mortensen O.H., van Kempen L.C., Jaattela M.;
RT "BIBX1382BS, but not AG1478 or PD153035, inhibits the ErbB kinases at
RT different concentrations in intact cells.";
RL Biochem. Biophys. Res. Commun. 281:25-31(2001).
RN [22]
RP MUTAGENESIS OF LYS-751, AND FUNCTION IN PROMOTING CELL DIFFERENTIATION AND
RP INHIBITING CELL PROLIFERATION.
RX PubMed=11390655; DOI=10.1128/mcb.21.13.4265-4275.2001;
RA Sartor C.I., Zhou H., Kozlowska E., Guttridge K., Kawata E., Caskey L.,
RA Harrelson J., Hynes N., Ethier S., Calvo B., Earp H.S. III;
RT "Her4 mediates ligand-dependent antiproliferative and differentiation
RT responses in human breast cancer cells.";
RL Mol. Cell. Biol. 21:4265-4275(2001).
RN [23]
RP FUNCTION, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION, INTERACTION WITH
RP YAP1, AND MUTAGENESIS OF TYR-1301.
RX PubMed=12807903; DOI=10.1074/jbc.m305597200;
RA Komuro A., Nagai M., Navin N.E., Sudol M.;
RT "WW domain-containing protein YAP associates with ErbB-4 and acts as a co-
RT transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that
RT translocates to the nucleus.";
RL J. Biol. Chem. 278:33334-33341(2003).
RN [24]
RP INTERACTION WITH MUC1.
RX PubMed=12939402;
RA Li Y., Yu W.-H., Ren J., Chen W., Huang L., Kharbanda S., Loda M., Kufe D.;
RT "Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent
RT on the DF3/MUC1 oncoprotein.";
RL Mol. Cancer Res. 1:765-775(2003).
RN [25]
RP INTERACTION WITH STAT5A, SUBCELLULAR LOCATION, FUNCTION IN NUCLEAR
RP LOCALIZATION OF STAT5A, DNA-BINDING, AND MUTAGENESIS OF 681-LYS--ARG-684.
RX PubMed=15534001; DOI=10.1083/jcb.200403155;
RA Williams C.C., Allison J.G., Vidal G.A., Burow M.E., Beckman B.S.,
RA Marrero L., Jones F.E.;
RT "The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by
RT functioning as a STAT5A nuclear chaperone.";
RL J. Cell Biol. 167:469-478(2004).
RN [26]
RP INTERACTION WITH WWOX, DOMAIN, AND MUTAGENESIS OF TYR-1035 AND TYR-1301.
RX PubMed=16061658; DOI=10.1158/0008-5472.can-05-1150;
RA Aqeilan R.I., Donati V., Palamarchuk A., Trapasso F., Kaou M., Pekarsky Y.,
RA Sudol M., Croce C.M.;
RT "WW domain-containing proteins, WWOX and YAP, compete for interaction with
RT ErbB-4 and modulate its transcriptional function.";
RL Cancer Res. 65:6764-6772(2005).
RN [27]
RP FUNCTION, PROTEOLYTIC PROCESSING, AND MUTAGENESIS OF VAL-675.
RX PubMed=15746097; DOI=10.1074/jbc.m412457200;
RA Vidal G.A., Naresh A., Marrero L., Jones F.E.;
RT "Presenilin-dependent gamma-secretase processing regulates multiple
RT ERBB4/HER4 activities.";
RL J. Biol. Chem. 280:19777-19783(2005).
RN [28]
RP FUNCTION IN PROMOTING APOPTOSIS, SUBCELLULAR LOCATION, AND INTERACTION WITH
RP BCL2.
RX PubMed=16778220; DOI=10.1158/0008-5472.can-05-2368;
RA Naresh A., Long W., Vidal G.A., Wimley W.C., Marrero L., Sartor C.I.,
RA Tovey S., Cooke T.G., Bartlett J.M., Jones F.E.;
RT "The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting
RT apoptosis of breast cancer cells.";
RL Cancer Res. 66:6412-6420(2006).
RN [29]
RP INTERACTION WITH CBFA2T3.
RX PubMed=16815842; DOI=10.1074/jbc.m603998200;
RA Linggi B., Carpenter G.;
RT "ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional
RT repression.";
RL J. Biol. Chem. 281:25373-25380(2006).
RN [30]
RP FUNCTION, PHOSPHORYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=16251361; DOI=10.1091/mbc.e05-05-0402;
RA Maatta J.A., Sundvall M., Junttila T.T., Peri L., Laine V.J., Isola J.,
RA Egeblad M., Elenius K.;
RT "Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4
RT isoform promote ligand-independent survival and cancer cell growth.";
RL Mol. Biol. Cell 17:67-79(2006).
RN [31]
RP FUNCTION IN DIFFERENTIATION OF MAMMARY EPITHELIUM, PROTEOLYTIC PROCESSING,
RP AUTOPHOSPHORYLATION, SUBCELLULAR LOCATION, AND INTERACTION WITH STAT5A.
RX PubMed=16837552; DOI=10.1091/mbc.e06-02-0101;
RA Muraoka-Cook R.S., Sandahl M., Husted C., Hunter D., Miraglia L.,
RA Feng S.M., Elenius K., Earp H.S. III;
RT "The intracellular domain of ErbB4 induces differentiation of mammary
RT epithelial cells.";
RL Mol. Biol. Cell 17:4118-4129(2006).
RN [32]
RP MUTAGENESIS OF GLN-646, AND PHOSPHORYLATION AT TYR-1056.
RX PubMed=17120616; DOI=10.3727/000000006783981134;
RA Pitfield S.E., Bryant I., Penington D.J., Park G., Riese D.J. II;
RT "Phosphorylation of ErbB4 on tyrosine 1056 is critical for ErbB4 coupling
RT to inhibition of colony formation by human mammary cell lines.";
RL Oncol. Res. 16:179-193(2006).
RN [33]
RP FUNCTION OF ERBB4 INTRACELLULAR DOMAIN, PROTEOLYTIC PROCESSING, SUBCELLULAR
RP LOCATION, UBIQUITINATION OF ERBB4 INTRACELLULAR DOMAIN, AND MUTAGENESIS OF
RP VAL-675; LYS-751; ARG-992; LEU-995 AND ASP-1000.
RX PubMed=17638867; DOI=10.1158/0008-5472.can-06-4145;
RA Strunk K.E., Husted C., Miraglia L.C., Sandahl M., Rearick W.A.,
RA Hunter D.M., Earp H.S. III, Muraoka-Cook R.S.;
RT "HER4 D-box sequences regulate mitotic progression and degradation of the
RT nuclear HER4 cleavage product s80HER4.";
RL Cancer Res. 67:6582-6590(2007).
RN [34]
RP INTERACTION WITH ERBB2, MUTAGENESIS OF ASP-843, AND AUTOPHOSPHORYLATION IN
RP TRANS.
RX PubMed=16978839; DOI=10.1016/j.cellsig.2006.07.020;
RA Li Z., Mei Y., Liu X., Zhou M.;
RT "Neuregulin-1 only induces trans-phosphorylation between ErbB receptor
RT heterodimer partners.";
RL Cell. Signal. 19:466-471(2007).
RN [35]
RP FUNCTION OF E4ICD, PHOSPHORYLATION, SUBCELLULAR LOCATION OF E4ICD, AND
RP MUTAGENESIS OF LYS-751.
RX PubMed=17486069; DOI=10.1038/sj.onc.1210501;
RA Sundvall M., Peri L., Maatta J.A., Tvorogov D., Paatero I., Savisalo M.,
RA Silvennoinen O., Yarden Y., Elenius K.;
RT "Differential nuclear localization and kinase activity of alternative ErbB4
RT intracellular domains.";
RL Oncogene 26:6905-6914(2007).
RN [36]
RP PHOSPHORYLATION AT TYR-875; TYR-1035; TYR-1056; TYR-1150; TYR-1162;
RP TYR-1188; TYR-1202; TYR-1242; TYR-1258 AND TYR-1284, INTERACTION WITH
RP PIK3R1 AND STAT1, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=18721752; DOI=10.1016/j.chembiol.2008.07.006;
RA Kaushansky A., Gordus A., Budnik B.A., Lane W.S., Rush J., MacBeath G.;
RT "System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation
RT that are unusually selective in their recruitment properties.";
RL Chem. Biol. 15:808-817(2008).
RN [37]
RP INTERACTION WITH NEDD4, SUBCELLULAR LOCATION, AND UBIQUITINATION OF E4ICD1.
RX PubMed=19193720; DOI=10.1096/fj.08-121947;
RA Zeng F., Xu J., Harris R.C.;
RT "Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK
RT II cells.";
RL FASEB J. 23:1935-1945(2009).
RN [38]
RP FUNCTION IN ACTIVATION OF SIGNALING PATHWAYS, INTERACTION WITH ERBB2,
RP CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, PHOSPHORYLATION BY ERBB2, ACTIVITY
RP REGULATION, AND MUTAGENESIS OF VAL-721; ALA-773; ARG-782; GLU-810; PRO-854;
RP ASP-861; GLU-872 AND THR-926.
RX PubMed=19098003; DOI=10.1074/jbc.m805438200;
RA Tvorogov D., Sundvall M., Kurppa K., Hollmen M., Repo S., Johnson M.S.,
RA Elenius K.;
RT "Somatic mutations of ErbB4: selective loss-of-function phenotype affecting
RT signal transduction pathways in cancer.";
RL J. Biol. Chem. 284:5582-5591(2009).
RN [39]
RP INTERACTION WITH WWP1, AND MUTAGENESIS OF TYR-1056 AND TYR-1301.
RX PubMed=19561640; DOI=10.1038/onc.2009.162;
RA Li Y., Zhou Z., Alimandi M., Chen C.;
RT "WW domain containing E3 ubiquitin protein ligase 1 targets the full-length
RT ErbB4 for ubiquitin-mediated degradation in breast cancer.";
RL Oncogene 28:2948-2958(2009).
RN [40]
RP INTERACTION WITH TXNL4A; DDX23; MATR3; RBM15; ILF3; TRIM28; U5S1; U2SURP;
RP ITCH; HNRNPU; AP2A1; NULC; LEO1; WWP2; MDM2; HXK1 AND SRRT, FUNCTION,
RP SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=20858735; DOI=10.1158/1541-7786.mcr-10-0042;
RA Gilmore-Hebert M., Ramabhadran R., Stern D.F.;
RT "Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage
RT response pathways.";
RL Mol. Cancer Res. 8:1388-1398(2010).
RN [41]
RP ACTIVITY REGULATION.
RX PubMed=21439954; DOI=10.1016/j.yexcr.2011.03.015;
RA Carrasco-Garcia E., Saceda M., Grasso S., Rocamora-Reverte L., Conde M.,
RA Gomez-Martinez A., Garcia-Morales P., Ferragut J.A., Martinez-Lacaci I.;
RT "Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting
RT with erbB3 and erbB4 in glioblastoma cell lines.";
RL Exp. Cell Res. 317:1476-1489(2011).
RN [42]
RP REVIEW ON ROLE IN BREAST AND NEURAL DEVELOPMENT.
RX PubMed=14504474;
RA Jones F.E., Golding J.P., Gassmann M.;
RT "ErbB4 signaling during breast and neural development: novel genetic models
RT reveal unique ErbB4 activities.";
RL Cell Cycle 2:555-559(2003).
RN [43]
RP REVIEW.
RX PubMed=15944951; DOI=10.14670/hh-20.1005;
RA Zaczek A., Brandt B., Bielawski K.P.;
RT "The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase
RT receptors and the consequences for therapeutic approaches.";
RL Histol. Histopathol. 20:1005-1015(2005).
RN [44]
RP REVIEW ON ROLE IN MAMMARY GLAND DEVELOPMENT.
RX PubMed=18437540; DOI=10.1007/s10911-008-9080-x;
RA Muraoka-Cook R.S., Feng S.M., Strunk K.E., Earp H.S. III;
RT "ErbB4/HER4: role in mammary gland development, differentiation and growth
RT inhibition.";
RL J. Mammary Gland Biol. Neoplasia 13:235-246(2008).
RN [45]
RP REVIEW ON ROLE OF THE ERBB4 INTRACELLULAR DOMAIN.
RX PubMed=18473151; DOI=10.1007/s10911-008-9076-6;
RA Jones F.E.;
RT "HER4 intracellular domain (4ICD) activity in the developing mammary gland
RT and breast cancer.";
RL J. Mammary Gland Biol. Neoplasia 13:247-258(2008).
RN [46]
RP REVIEW ON LIGAND SPECIFICITY AND SIGNALING.
RX PubMed=18454307; DOI=10.1007/s10911-008-9079-3;
RA Sundvall M., Iljin K., Kilpinen S., Sara H., Kallioniemi O.P., Elenius K.;
RT "Role of ErbB4 in breast cancer.";
RL J. Mammary Gland Biol. Neoplasia 13:259-268(2008).
RN [47]
RP REVIEW ON ROLE IN NRG1 SIGNALING AND CARDIOVASCULAR HEALTH.
RX PubMed=20933198; DOI=10.1016/s1054-3589(10)59002-1;
RA Xu Y., Li X., Liu X., Zhou M.;
RT "Neuregulin-1/ErbB signaling and chronic heart failure.";
RL Adv. Pharmacol. 59:31-51(2010).
RN [48]
RP REVIEW ON ALTERNATIVE SPLICING AND PROTEOLYTIC PROCESSING; TISSUE
RP SPECIFICITY; SIGNALING AND ROLE IN DISEASE.
RX PubMed=21811097; DOI=10.4161/cc.10.16.17194;
RA Veikkolainen V., Vaparanta K., Halkilahti K., Iljin K., Sundvall M.,
RA Elenius K.;
RT "Function of ERBB4 is determined by alternative splicing.";
RL Cell Cycle 10:2647-2657(2011).
RN [49]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 26-641, DISULFIDE BONDS, AND
RP GLYCOSYLATION AT ASN-138; ASN-174; ASN-253; ASN-358; ASN-410; ASN-473;
RP ASN-495 AND ASN-576.
RX PubMed=16203964; DOI=10.1073/pnas.0507591102;
RA Bouyain S., Longo P.A., Li S., Ferguson K.M., Leahy D.J.;
RT "The extracellular region of ErbB4 adopts a tethered conformation in the
RT absence of ligand.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:15024-15029(2005).
RN [50]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 690-999 IN COMPLEX WITH INHIBITOR,
RP CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF LEU-710;
RP MET-766; LEU-864 AND ILE-947.
RX PubMed=18287036; DOI=10.1073/pnas.0708281105;
RA Wood E.R., Shewchuk L.M., Ellis B., Brignola P., Brashear R.L.,
RA Caferro T.R., Dickerson S.H., Dickson H.D., Donaldson K.H., Gaul M.,
RA Griffin R.J., Hassell A.M., Keith B., Mullin R., Petrov K.G., Reno M.J.,
RA Rusnak D.W., Tadepalli S.M., Ulrich J.C., Wagner C.D., Vanderwall D.E.,
RA Waterson A.G., Williams J.D., White W.L., Uehling D.E.;
RT "6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as
RT tunable covalent modifiers of ErbB kinases.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:2773-2778(2008).
RN [51]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 702-1029 OF APOPROTEIN AND IN
RP COMPLEX WITH LAPATINIB, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP AUTOPHOSPHORYLATION, AND SUBUNIT.
RX PubMed=18334220; DOI=10.1016/j.str.2007.12.016;
RA Qiu C., Tarrant M.K., Choi S.H., Sathyamurthy A., Bose R., Banjade S.,
RA Pal A., Bornmann W.G., Lemmon M.A., Cole P.A., Leahy D.J.;
RT "Mechanism of activation and inhibition of the HER4/ErbB4 kinase.";
RL Structure 16:460-467(2008).
RN [52]
RP VARIANTS [LARGE SCALE ANALYSIS] ILE-140 AND TYR-303.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [53]
RP VARIANTS ALS19 GLN-927 AND TRP-1275, AND CHARACTERIZATION OF VARIANTS ASL19
RP GLN-927 AND TRP-1275.
RX PubMed=24119685; DOI=10.1016/j.ajhg.2013.09.008;
RA Takahashi Y., Fukuda Y., Yoshimura J., Toyoda A., Kurppa K., Moritoyo H.,
RA Belzil V.V., Dion P.A., Higasa K., Doi K., Ishiura H., Mitsui J., Date H.,
RA Ahsan B., Matsukawa T., Ichikawa Y., Moritoyo T., Ikoma M., Hashimoto T.,
RA Kimura F., Murayama S., Onodera O., Nishizawa M., Yoshida M., Atsuta N.,
RA Sobue G., Fifita J.A., Williams K.L., Blair I.P., Nicholson G.A.,
RA Gonzalez-Perez P., Brown R.H. Jr., Nomoto M., Elenius K., Rouleau G.A.,
RA Fujiyama A., Morishita S., Goto J., Tsuji S., Nakamura R., Watanabe H.,
RA Izumi Y., Kaji R., Morita M., Ogaki K., Taniguchi A., Aiba I.,
RA Mizoguchi K., Okamoto K., Hasegawa K., Aoki M., Kawata A., Nakano I.,
RA Abe K., Oda M., Konagaya M., Imai T., Nakagawa M., Fujita T., Sasaki H.,
RA Nishizawa M.;
RT "ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause
RT amyotrophic lateral sclerosis type 19.";
RL Am. J. Hum. Genet. 93:900-905(2013).
CC -!- FUNCTION: Tyrosine-protein kinase that plays an essential role as cell
CC surface receptor for neuregulins and EGF family members and regulates
CC development of the heart, the central nervous system and the mammary
CC gland, gene transcription, cell proliferation, differentiation,
CC migration and apoptosis. Required for normal cardiac muscle
CC differentiation during embryonic development, and for postnatal
CC cardiomyocyte proliferation. Required for normal development of the
CC embryonic central nervous system, especially for normal neural crest
CC cell migration and normal axon guidance. Required for mammary gland
CC differentiation, induction of milk proteins and lactation. Acts as
CC cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and
CC the EGF family members BTC, EREG and HBEGF. Ligand binding triggers
CC receptor dimerization and autophosphorylation at specific tyrosine
CC residues that then serve as binding sites for scaffold proteins and
CC effectors. Ligand specificity and signaling is modulated by alternative
CC splicing, proteolytic processing, and by the formation of heterodimers
CC with other ERBB family members, thereby creating multiple combinations
CC of intracellular phosphotyrosines that trigger ligand- and context-
CC specific cellular responses. Mediates phosphorylation of SHC1 and
CC activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A
CC CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the
CC activation of phosphatidylinositol 3-kinase and AKT1 and protect cells
CC against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate
CC reorganization of the actin cytoskeleton and promote cell migration in
CC response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the
CC phosphotyrosine that mediates interaction with PIK3R1, and hence do not
CC phosphorylate PIK3R1, do not protect cells against apoptosis, and do
CC not promote reorganization of the actin cytoskeleton and cell
CC migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-
CC A CYT-2 gives rise to the corresponding soluble intracellular domains
CC (4ICD) that translocate to the nucleus, promote nuclear import of
CC STAT5A, activation of STAT5A, mammary epithelium differentiation, cell
CC proliferation and activation of gene expression. The ERBB4 soluble
CC intracellular domains (4ICD) colocalize with STAT5A at the CSN2
CC promoter to regulate transcription of milk proteins during lactation.
CC The ERBB4 soluble intracellular domains can also translocate to
CC mitochondria and promote apoptosis. {ECO:0000269|PubMed:10348342,
CC ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:10358079,
CC ECO:0000269|PubMed:10722704, ECO:0000269|PubMed:10867024,
CC ECO:0000269|PubMed:11178955, ECO:0000269|PubMed:11390655,
CC ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001,
CC ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:16251361,
CC ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552,
CC ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867,
CC ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:20858735,
CC ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:8617750,
CC ECO:0000269|PubMed:9135143, ECO:0000269|PubMed:9168115,
CC ECO:0000269|PubMed:9334263}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028,
CC ECO:0000269|PubMed:18287036, ECO:0000269|PubMed:18334220,
CC ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:8617750};
CC -!- ACTIVITY REGULATION: Binding of a cognate ligand leads to dimerization
CC and activation by autophosphorylation on tyrosine residues. In vitro
CC kinase activity is increased by Mg(2+). Inhibited by PD153035,
CC lapatinib, gefitinib (iressa, ZD1839), AG1478 and BIBX1382BS.
CC {ECO:0000269|PubMed:11178955, ECO:0000269|PubMed:18334220,
CC ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:21439954,
CC ECO:0000269|PubMed:8617750}.
CC -!- SUBUNIT: Monomer in the absence of bound ligand. Homodimer or
CC heterodimer with another ERBB family member upon ligand binding, thus
CC forming heterotetramers. Interacts with EGFR and ERBB2. Interacts with
CC CBFA2T3 (By similarity). Interacts with DLG2 (via its PDZ domain), DLG3
CC (via its PDZ domain), DLG4 (via its PDZ domain) and SNTB2 (via its PDZ
CC domain). Interacts with MUC1. Interacts (via its PPxy motifs) with
CC WWOX. Interacts (via the PPxY motif 3 of isoform JM-A CYT-2) with YAP1
CC (via the WW domain 1 of isoform 1). Interacts (isoform JM-A CYT-1 and
CC isoform JM-B CYT-1) with WWP1. Interacts (via its intracellular domain)
CC with TRIM28. Interacts (via the intracellular domains of both CYT-1 and
CC CYT-2 isoforms) with KAP1; the interaction does not phosphorylate KAP1
CC but represses ERBB4-mediated transcriptional activity. Interacts with
CC PRPU, DDX23, MATR3, RBM15, ILF3, KAP1, U5S1, U2SURP, ITCH, HNRNPU,
CC AP2A1, NULC, LEO1, WWP2, IGHG1, HXK1, GRB7 AND SRRT. Interacts
CC (phosphorylated isoform JM-A CYT-1 and isoform JM-B CYT-1) with PIK3R1.
CC Interacts with SHC1. Interacts with GRB2. Interacts (soluble
CC intracellular domain) with STAT5A. Interacts (soluble intracellular
CC domain) with BCL2. Interacts (phosphorylated) with STAT1. {ECO:0000250,
CC ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:10353604,
CC ECO:0000269|PubMed:10358079, ECO:0000269|PubMed:10725395,
CC ECO:0000269|PubMed:10867024, ECO:0000269|PubMed:12807903,
CC ECO:0000269|PubMed:12939402, ECO:0000269|PubMed:15534001,
CC ECO:0000269|PubMed:16061658, ECO:0000269|PubMed:16778220,
CC ECO:0000269|PubMed:16815842, ECO:0000269|PubMed:16837552,
CC ECO:0000269|PubMed:16978839, ECO:0000269|PubMed:18287036,
CC ECO:0000269|PubMed:18334220, ECO:0000269|PubMed:18721752,
CC ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:19193720,
CC ECO:0000269|PubMed:19561640, ECO:0000269|PubMed:20858735,
CC ECO:0000269|PubMed:7689552, ECO:0000269|PubMed:7902537,
CC ECO:0000269|PubMed:8570211, ECO:0000269|PubMed:8617750,
CC ECO:0000269|PubMed:9135143, ECO:0000269|PubMed:9168115,
CC ECO:0000269|PubMed:9275162, ECO:0000269|PubMed:9419975,
CC ECO:0000269|PubMed:9516479}.
CC -!- INTERACTION:
CC Q15303; P42684: ABL2; NbExp=4; IntAct=EBI-80371, EBI-1102694;
CC Q15303; Q13895: BYSL; NbExp=3; IntAct=EBI-80371, EBI-358049;
CC Q15303; P78352: DLG4; NbExp=6; IntAct=EBI-80371, EBI-80389;
CC Q15303; P00533: EGFR; NbExp=2; IntAct=EBI-80371, EBI-297353;
CC Q15303; P04626: ERBB2; NbExp=4; IntAct=EBI-80371, EBI-641062;
CC Q15303; P21860: ERBB3; NbExp=4; IntAct=EBI-80371, EBI-720706;
CC Q15303; Q99075: HBEGF; NbExp=2; IntAct=EBI-80371, EBI-7211558;
CC Q15303; P08238: HSP90AB1; NbExp=2; IntAct=EBI-80371, EBI-352572;
CC Q15303; Q96J02-2: ITCH; NbExp=3; IntAct=EBI-80371, EBI-6672198;
CC Q15303; Q96JA1: LRIG1; NbExp=3; IntAct=EBI-80371, EBI-2865191;
CC Q15303; Q02297-6: NRG1; NbExp=3; IntAct=EBI-80371, EBI-15651799;
CC Q15303; P26447: S100A4; NbExp=4; IntAct=EBI-80371, EBI-717058;
CC Q15303; P29353: SHC1; NbExp=2; IntAct=EBI-80371, EBI-78835;
CC Q15303; Q12815: TROAP; NbExp=3; IntAct=EBI-80371, EBI-2349743;
CC Q15303; P46937: YAP1; NbExp=4; IntAct=EBI-80371, EBI-1044059;
CC Q15303-3; Q96J02-2: ITCH; NbExp=2; IntAct=EBI-15692884, EBI-6672198;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10348342,
CC ECO:0000269|PubMed:12807903, ECO:0000269|PubMed:15534001,
CC ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:16778220,
CC ECO:0000269|PubMed:16837552, ECO:0000269|PubMed:17486069,
CC ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:19193720,
CC ECO:0000269|PubMed:20858735, ECO:0000269|PubMed:8383326,
CC ECO:0000269|PubMed:9334263}; Single-pass type I membrane protein
CC {ECO:0000269|PubMed:10348342, ECO:0000269|PubMed:12807903,
CC ECO:0000269|PubMed:15534001, ECO:0000269|PubMed:16251361,
CC ECO:0000269|PubMed:16778220, ECO:0000269|PubMed:16837552,
CC ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867,
CC ECO:0000269|PubMed:19193720, ECO:0000269|PubMed:20858735,
CC ECO:0000269|PubMed:8383326, ECO:0000269|PubMed:9334263}. Note=In
CC response to NRG1 treatment, the activated receptor is internalized.
CC -!- SUBCELLULAR LOCATION: [ERBB4 intracellular domain]: Nucleus
CC {ECO:0000269|PubMed:17486069}. Mitochondrion
CC {ECO:0000269|PubMed:17486069}. Note=Following proteolytical processing
CC E4ICD (E4ICD1 or E4ICD2 generated from the respective isoforms) is
CC translocated to the nucleus. Significantly more E4ICD2 than E4ICD1 is
CC found in the nucleus. E4ICD2 colocalizes with YAP1 in the nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=JM-A CYT-1;
CC IsoId=Q15303-1; Sequence=Displayed;
CC Name=JM-B CYT-1;
CC IsoId=Q15303-2; Sequence=VSP_002895;
CC Name=JM-A CYT-2;
CC IsoId=Q15303-3; Sequence=VSP_022148;
CC Name=JM-B CYT-2;
CC IsoId=Q15303-4; Sequence=VSP_002895, VSP_022148;
CC -!- TISSUE SPECIFICITY: Expressed at highest levels in brain, heart,
CC kidney, in addition to skeletal muscle, parathyroid, cerebellum,
CC pituitary, spleen, testis and breast. Lower levels in thymus, lung,
CC salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1
CC are expressed in cerebellum, but only the isoform JM-B is expressed in
CC the heart. {ECO:0000269|PubMed:10353604, ECO:0000269|PubMed:8383326,
CC ECO:0000269|PubMed:9334263}.
CC -!- PTM: Isoform JM-A CYT-1 and isoform JM-A CYT-2 are processed by ADAM17.
CC Proteolytic processing in response to ligand or 12-O-
CC tetradecanoylphorbol-13-acetate stimulation results in the production
CC of 120 kDa soluble receptor forms and intermediate membrane-anchored 80
CC kDa fragments (m80HER4), which are further processed by a presenilin-
CC dependent gamma-secretase to release a cytoplasmic intracellular domain
CC (E4ICD; E4ICD1/s80Cyt1 or E4ICD2/s80Cyt2, depending on the isoform).
CC Membrane-anchored 80 kDa fragments of the processed isoform JM-A CYT-1
CC are more readily degraded by the proteasome than fragments of isoform
CC JM-A CYT-2, suggesting a prevalence of E4ICD2 over E4ICD1. Isoform JM-B
CC CYT-1 and isoform JM-B CYT-2 lack the ADAM17 cleavage site and are not
CC processed by ADAM17, precluding further processing by gamma-secretase.
CC {ECO:0000269|PubMed:10744726, ECO:0000269|PubMed:12807903,
CC ECO:0000269|PubMed:15746097, ECO:0000269|PubMed:16837552,
CC ECO:0000269|PubMed:17638867, ECO:0000269|PubMed:9334263}.
CC -!- PTM: Autophosphorylated on tyrosine residues in response to ligand
CC binding. Autophosphorylation occurs in trans, i.e. one subunit of the
CC dimeric receptor phosphorylates tyrosine residues on the other subunit.
CC Ligands trigger phosphorylation at specific tyrosine residues, thereby
CC creating binding sites for scaffold proteins and effectors.
CC Constitutively phosphorylated at a basal level when overexpressed in
CC heterologous systems; ligand binding leads to increased
CC phosphorylation. Phosphorylation at Tyr-1035 is important for
CC interaction with STAT1. Phosphorylation at Tyr-1056 is important for
CC interaction with PIK3R1. Phosphorylation at Tyr-1242 is important for
CC interaction with SHC1. Phosphorylation at Tyr-1188 may also contribute
CC to the interaction with SHC1. Isoform JM-A CYT-2 is constitutively
CC phosphorylated on tyrosine residues in a ligand-independent manner.
CC E4ICD2 but not E4ICD1 is phosphorylated on tyrosine residues.
CC {ECO:0000269|PubMed:16251361, ECO:0000269|PubMed:17120616,
CC ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:18721752,
CC ECO:0000269|PubMed:19098003, ECO:0000269|PubMed:8617750,
CC ECO:0000269|PubMed:9168115}.
CC -!- PTM: Ubiquitinated. During mitosis, the ERBB4 intracellular domain is
CC ubiquitinated by the APC/C complex and targeted to proteasomal
CC degradation. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are
CC ubiquitinated by WWP1. The ERBB4 intracellular domain (E4ICD1) is
CC ubiquitinated, and this involves NEDD4. {ECO:0000269|PubMed:17638867,
CC ECO:0000269|PubMed:19193720}.
CC -!- DISEASE: Amyotrophic lateral sclerosis 19 (ALS19) [MIM:615515]: A
CC neurodegenerative disorder affecting upper motor neurons in the brain
CC and lower motor neurons in the brain stem and spinal cord, resulting in
CC fatal paralysis. Sensory abnormalities are absent. The pathologic
CC hallmarks of the disease include pallor of the corticospinal tract due
CC to loss of motor neurons, presence of ubiquitin-positive inclusions
CC within surviving motor neurons, and deposition of pathologic
CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to
CC be multifactorial, involving both genetic and environmental factors.
CC The disease is inherited in 5-10% of the cases.
CC {ECO:0000269|PubMed:24119685}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform JM-A CYT-1]: Proteolytical processing generates
CC E4ICD1 (s80Cyt1).
CC -!- MISCELLANEOUS: [Isoform JM-A CYT-2]: Proteolytical processing generates
CC E4ICD2 (s80Cyt2). {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. EGF receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
CC -!- CAUTION: Conflicting reports about the role of ERBB4 in mediating
CC apoptosis, differentiation, or tumor cell proliferation may be
CC explained by the opposite functions of the different isoforms and their
CC intracellular fragments, and by the formation of heterodimers with
CC other EGF receptor family members (PubMed:18454307 and
CC PubMed:21811097). Thus, heterodimer formation of a kinase-dead ERBB4
CC mutant with ERBB2 is sufficient for the activation of AKT1, MAPK1/ERK2
CC and MAPK3/ERK1 (PubMed:19098003). {ECO:0000305|PubMed:19098003}.
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DR EMBL; L07868; AAB59446.1; -; mRNA.
DR EMBL; BC112199; AAI12200.1; -; mRNA.
DR EMBL; BC143741; AAI43742.1; -; mRNA.
DR EMBL; BC143747; AAI43748.1; -; mRNA.
DR EMBL; BC143749; AAI43750.1; -; mRNA.
DR EMBL; AB209697; BAD92934.1; -; mRNA.
DR CCDS; CCDS2394.1; -. [Q15303-1]
DR CCDS; CCDS42811.1; -. [Q15303-3]
DR PIR; A47253; A47253.
DR RefSeq; NP_001036064.1; NM_001042599.1. [Q15303-3]
DR RefSeq; NP_005226.1; NM_005235.2. [Q15303-1]
DR RefSeq; XP_005246433.1; XM_005246376.2. [Q15303-2]
DR RefSeq; XP_005246434.1; XM_005246377.2. [Q15303-4]
DR PDB; 2AHX; X-ray; 2.40 A; A/B=26-641.
DR PDB; 2L2T; NMR; -; A/B=642-685.
DR PDB; 2LCX; NMR; -; A/B=642-685.
DR PDB; 2R4B; X-ray; 2.40 A; A/B=690-999.
DR PDB; 3BBT; X-ray; 2.80 A; B/D=702-1029.
DR PDB; 3BBW; X-ray; 4.00 A; A/B=702-1029.
DR PDB; 3BCE; X-ray; 2.50 A; A/B/C=702-1029.
DR PDB; 3U2P; X-ray; 2.57 A; A=26-522.
DR PDB; 3U7U; X-ray; 3.03 A; A/B/C/D/E/F=26-640.
DR PDB; 3U9U; X-ray; 3.42 A; E/F=26-650.
DR PDBsum; 2AHX; -.
DR PDBsum; 2L2T; -.
DR PDBsum; 2LCX; -.
DR PDBsum; 2R4B; -.
DR PDBsum; 3BBT; -.
DR PDBsum; 3BBW; -.
DR PDBsum; 3BCE; -.
DR PDBsum; 3U2P; -.
DR PDBsum; 3U7U; -.
DR PDBsum; 3U9U; -.
DR AlphaFoldDB; Q15303; -.
DR SMR; Q15303; -.
DR BioGRID; 108378; 172.
DR DIP; DIP-29650N; -.
DR ELM; Q15303; -.
DR IntAct; Q15303; 106.
DR MINT; Q15303; -.
DR STRING; 9606.ENSP00000342235; -.
DR BindingDB; Q15303; -.
DR ChEMBL; CHEMBL3009; -.
DR DrugBank; DB08916; Afatinib.
DR DrugBank; DB12267; Brigatinib.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB15035; Zanubrutinib.
DR DrugCentral; Q15303; -.
DR GuidetoPHARMACOLOGY; 1799; -.
DR TCDB; 8.A.23.1.17; the basigin (basigin) family.
DR GlyGen; Q15303; 11 sites.
DR iPTMnet; Q15303; -.
DR PhosphoSitePlus; Q15303; -.
DR BioMuta; ERBB4; -.
DR DMDM; 3913590; -.
DR jPOST; Q15303; -.
DR MassIVE; Q15303; -.
DR MaxQB; Q15303; -.
DR PaxDb; Q15303; -.
DR PeptideAtlas; Q15303; -.
DR PRIDE; Q15303; -.
DR ProteomicsDB; 60520; -. [Q15303-1]
DR ProteomicsDB; 60521; -. [Q15303-2]
DR ProteomicsDB; 60522; -. [Q15303-3]
DR ProteomicsDB; 60523; -. [Q15303-4]
DR ABCD; Q15303; 1 sequenced antibody.
DR Antibodypedia; 1602; 1470 antibodies from 46 providers.
DR DNASU; 2066; -.
DR Ensembl; ENST00000342788.9; ENSP00000342235.4; ENSG00000178568.15. [Q15303-1]
DR Ensembl; ENST00000436443.5; ENSP00000403204.1; ENSG00000178568.15. [Q15303-3]
DR GeneID; 2066; -.
DR KEGG; hsa:2066; -.
DR MANE-Select; ENST00000342788.9; ENSP00000342235.4; NM_005235.3; NP_005226.1.
DR UCSC; uc002veg.2; human. [Q15303-1]
DR CTD; 2066; -.
DR DisGeNET; 2066; -.
DR GeneCards; ERBB4; -.
DR HGNC; HGNC:3432; ERBB4.
DR HPA; ENSG00000178568; Tissue enhanced (brain, fallopian tube).
DR MalaCards; ERBB4; -.
DR MIM; 600543; gene.
DR MIM; 615515; phenotype.
DR neXtProt; NX_Q15303; -.
DR OpenTargets; ENSG00000178568; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 178469; Autosomal dominant non-syndromic intellectual disability.
DR PharmGKB; PA27847; -.
DR VEuPathDB; HostDB:ENSG00000178568; -.
DR eggNOG; KOG1025; Eukaryota.
DR GeneTree; ENSGT00940000154695; -.
DR InParanoid; Q15303; -.
DR OMA; XEALIMA; -.
DR OrthoDB; 81952at2759; -.
DR PhylomeDB; Q15303; -.
DR TreeFam; TF106002; -.
DR BRENDA; 2.7.10.1; 2681.
DR PathwayCommons; Q15303; -.
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-1253288; Downregulation of ERBB4 signaling.
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-9018519; Estrogen-dependent gene expression.
DR Reactome; R-HSA-9620244; Long-term potentiation.
DR Reactome; R-HSA-9664565; Signaling by ERBB2 KD Mutants.
DR Reactome; R-HSA-9665686; Signaling by ERBB2 TMD/JMD mutants.
DR SignaLink; Q15303; -.
DR SIGNOR; Q15303; -.
DR BioGRID-ORCS; 2066; 32 hits in 1103 CRISPR screens.
DR ChiTaRS; ERBB4; human.
DR EvolutionaryTrace; Q15303; -.
DR GeneWiki; ERBB4; -.
DR GenomeRNAi; 2066; -.
DR Pharos; Q15303; Tclin.
DR PRO; PR:Q15303; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q15303; protein.
DR Bgee; ENSG00000178568; Expressed in endothelial cell and 152 other tissues.
DR ExpressionAtlas; Q15303; baseline and differential.
DR Genevisible; Q15303; HS.
DR GO; GO:0009925; C:basal plasma membrane; IBA:GO_Central.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0098982; C:GABA-ergic synapse; IEA:Ensembl.
DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0099061; C:integral component of postsynaptic density membrane; IEA:Ensembl.
DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0045211; C:postsynaptic membrane; ISS:UniProtKB.
DR GO; GO:0043235; C:receptor complex; IDA:MGI.
DR GO; GO:0044214; C:spanning component of plasma membrane; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005006; F:epidermal growth factor receptor activity; IEA:Ensembl.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; IPI:UniProtKB.
DR GO; GO:0050811; F:GABA receptor binding; IEA:Ensembl.
DR GO; GO:0038131; F:neuregulin receptor activity; IDA:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0030296; F:protein tyrosine kinase activator activity; IEA:Ensembl.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IMP:UniProtKB.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0061026; P:cardiac muscle tissue regeneration; ISS:UniProtKB.
DR GO; GO:0045165; P:cell fate commitment; IEA:Ensembl.
DR GO; GO:0016477; P:cell migration; IDA:UniProtKB.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IEA:Ensembl.
DR GO; GO:0021551; P:central nervous system morphogenesis; ISS:UniProtKB.
DR GO; GO:0009880; P:embryonic pattern specification; ISS:UniProtKB.
DR GO; GO:0038135; P:ERBB2-ERBB4 signaling pathway; IEA:Ensembl.
DR GO; GO:0038130; P:ERBB4 signaling pathway; IDA:MGI.
DR GO; GO:0038138; P:ERBB4-ERBB4 signaling pathway; IDA:MGI.
DR GO; GO:0072046; P:establishment of planar polarity involved in nephron morphogenesis; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; ISS:UniProtKB.
DR GO; GO:0007595; P:lactation; IMP:UniProtKB.
DR GO; GO:0060749; P:mammary gland alveolus development; ISS:UniProtKB.
DR GO; GO:0060644; P:mammary gland epithelial cell differentiation; ISS:UniProtKB.
DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IMP:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0007399; P:nervous system development; ISS:UniProtKB.
DR GO; GO:0001755; P:neural crest cell migration; ISS:UniProtKB.
DR GO; GO:0021889; P:olfactory bulb interneuron differentiation; ISS:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0060045; P:positive regulation of cardiac muscle cell proliferation; ISS:UniProtKB.
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:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; IDA:UniProtKB.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IEA:Ensembl.
DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; TAS:UniProtKB.
DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; IMP:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:UniProtKB.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IMP:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0030334; P:regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IDA:UniProtKB.
DR GO; GO:0007416; P:synapse assembly; IEA:Ensembl.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IDA:UniProtKB.
DR CDD; cd00064; FU; 3.
DR Gene3D; 3.80.20.20; -; 2.
DR InterPro; IPR006211; Furin-like_Cys-rich_dom.
DR InterPro; IPR006212; Furin_repeat.
DR InterPro; IPR032778; GF_recep_IV.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR000494; Rcpt_L-dom.
DR InterPro; IPR036941; Rcpt_L-dom_sf.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016245; Tyr_kinase_EGF/ERB/XmrK_rcpt.
DR Pfam; PF00757; Furin-like; 1.
DR Pfam; PF14843; GF_recep_IV; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF01030; Recep_L_domain; 2.
DR PIRSF; PIRSF000619; TyrPK_EGF-R; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00261; FU; 5.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57184; SSF57184; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing;
KW Amyotrophic lateral sclerosis; Apoptosis; ATP-binding; Cell membrane;
KW Developmental protein; Disease variant; Disulfide bond; Glycoprotein;
KW Kinase; Lactation; Membrane; Mitochondrion; Neurodegeneration;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Receptor; Reference proteome;
KW Repeat; Signal; Transcription; Transcription regulation; Transferase;
KW Transmembrane; Transmembrane helix; Tyrosine-protein kinase;
KW Ubl conjugation.
FT SIGNAL 1..25
FT /evidence="ECO:0000255"
FT CHAIN 26..1308
FT /note="Receptor tyrosine-protein kinase erbB-4"
FT /id="PRO_0000016674"
FT CHAIN 676..1308
FT /note="ERBB4 intracellular domain"
FT /evidence="ECO:0000250"
FT /id="PRO_0000396797"
FT TOPO_DOM 26..651
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 652..675
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 676..1308
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 718..985
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1117..1150
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 676..684
FT /note="Nuclear localization signal"
FT MOTIF 1032..1035
FT /note="PPxY motif 1"
FT MOTIF 1053..1056
FT /note="PPxY motif 2"
FT MOTIF 1298..1301
FT /note="PPxY motif 3"
FT MOTIF 1306..1308
FT /note="PDZ-binding"
FT ACT_SITE 843
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 724..732
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 751
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 797..799
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 843..848
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 875
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18721752"
FT MOD_RES 1035
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18721752"
FT MOD_RES 1056
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:17120616,
FT ECO:0000269|PubMed:18721752, ECO:0000269|PubMed:8617750"
FT MOD_RES 1150
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18721752"
FT MOD_RES 1162
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18721752"
FT MOD_RES 1188
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18721752,
FT ECO:0000269|PubMed:8617750"
FT MOD_RES 1202
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18721752"
FT MOD_RES 1242
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18721752,
FT ECO:0000269|PubMed:8617750"
FT MOD_RES 1258
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18721752"
FT MOD_RES 1284
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:18721752"
FT CARBOHYD 138
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16203964"
FT CARBOHYD 174
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16203964"
FT CARBOHYD 181
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 253
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16203964"
FT CARBOHYD 358
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16203964"
FT CARBOHYD 410
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16203964"
FT CARBOHYD 473
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16203964"
FT CARBOHYD 495
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16203964"
FT CARBOHYD 548
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 576
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16203964"
FT CARBOHYD 620
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 29..56
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 156..186
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 189..197
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 193..205
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 213..221
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 217..229
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 230..238
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 234..246
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 249..258
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 262..289
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 293..304
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 308..323
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 326..330
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 503..512
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 507..520
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 523..532
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 536..552
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 555..569
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 559..577
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 580..589
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 593..614
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 617..625
FT /evidence="ECO:0000269|PubMed:16203964"
FT DISULFID 621..633
FT /evidence="ECO:0000269|PubMed:16203964"
FT VAR_SEQ 626..648
FT /note="NGPTSHDCIYYPWTGHSTLPQHA -> IGSSIEDCIGLMD (in isoform
FT JM-B CYT-1 and isoform JM-B CYT-2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9334263"
FT /id="VSP_002895"
FT VAR_SEQ 1046..1061
FT /note="Missing (in isoform JM-A CYT-2 and isoform JM-B CYT-
FT 2)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.4"
FT /id="VSP_022148"
FT VARIANT 140
FT /note="T -> I (in a colorectal adenocarcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042113"
FT VARIANT 303
FT /note="S -> Y (in a lung squamous cell carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042114"
FT VARIANT 927
FT /note="R -> Q (in ALS19; reduces autophosphorylation upon
FT NRG1 stimulation; dbSNP:rs397514262)"
FT /evidence="ECO:0000269|PubMed:24119685"
FT /id="VAR_070810"
FT VARIANT 1275
FT /note="R -> W (in ALS19; reduces autophosphorylation upon
FT NRG1 stimulation; dbSNP:rs397514263)"
FT /evidence="ECO:0000269|PubMed:24119685"
FT /id="VAR_070811"
FT MUTAGEN 646
FT /note="Q->C: Constitutively activated kinase."
FT /evidence="ECO:0000269|PubMed:17120616"
FT MUTAGEN 675
FT /note="V->A: Abolishes proteolytic processing and nuclear
FT localization."
FT /evidence="ECO:0000269|PubMed:15746097,
FT ECO:0000269|PubMed:17638867"
FT MUTAGEN 681..684
FT /note="KKKR->EIMG: Abolishes nuclear localization of the
FT ERBB4 intracellular domain."
FT /evidence="ECO:0000269|PubMed:15534001"
FT MUTAGEN 710
FT /note="L->N: Strongly reduced autophosphorylation."
FT /evidence="ECO:0000269|PubMed:18287036"
FT MUTAGEN 721
FT /note="V->I: No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:19098003"
FT MUTAGEN 751
FT /note="K->R: Abolishes kinase activity. Abolishes
FT phosphorylation, proteolytic processing and nuclear
FT localization."
FT /evidence="ECO:0000269|PubMed:11390655,
FT ECO:0000269|PubMed:17486069, ECO:0000269|PubMed:17638867"
FT MUTAGEN 766
FT /note="M->R: Strongly reduced autophosphorylation."
FT /evidence="ECO:0000269|PubMed:18287036"
FT MUTAGEN 773
FT /note="A->S: No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:19098003"
FT MUTAGEN 782
FT /note="R->Q: No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:19098003"
FT MUTAGEN 810
FT /note="E->K: No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:19098003"
FT MUTAGEN 843
FT /note="D->N: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:16978839"
FT MUTAGEN 854
FT /note="P->Q: No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:19098003"
FT MUTAGEN 861
FT /note="D->Y: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:19098003"
FT MUTAGEN 864
FT /note="L->R: Strongly reduced autophosphorylation."
FT /evidence="ECO:0000269|PubMed:18287036"
FT MUTAGEN 872
FT /note="E->K: No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:19098003"
FT MUTAGEN 926
FT /note="T->M: No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:19098003"
FT MUTAGEN 947
FT /note="I->R: Constitutively autophosphorylated."
FT /evidence="ECO:0000269|PubMed:18287036"
FT MUTAGEN 992
FT /note="R->A: Abolishes APC/C-mediated degradation; when
FT associated with A-995 and A-1000."
FT /evidence="ECO:0000269|PubMed:17638867"
FT MUTAGEN 995
FT /note="L->A: Abolishes APC/C-mediated degradation; when
FT associated with A-992 and A-1000."
FT /evidence="ECO:0000269|PubMed:17638867"
FT MUTAGEN 1000
FT /note="D->A: Abolishes APC/C-mediated degradation; when
FT associated with A-992 and A-995."
FT /evidence="ECO:0000269|PubMed:17638867"
FT MUTAGEN 1035
FT /note="Y->A: No effect on interaction with WWOX. Abolishes
FT interaction with WWOX; when associated with A-1301."
FT /evidence="ECO:0000269|PubMed:16061658"
FT MUTAGEN 1056
FT /note="Y->A: Abolishes interaction with NEDD4 and impairs
FT ubiquitination. Promotes nuclear translocation of ERBB4
FT intracellular domain E4ICD1."
FT /evidence="ECO:0000269|PubMed:19561640"
FT MUTAGEN 1056
FT /note="Y->F: Abolishes interaction with WWP1; when
FT associated with F-1301."
FT /evidence="ECO:0000269|PubMed:19561640"
FT MUTAGEN 1301
FT /note="Y->A: Abolishes interaction with NEDD4 and impairs
FT ubiquitination."
FT /evidence="ECO:0000269|PubMed:12807903,
FT ECO:0000269|PubMed:16061658, ECO:0000269|PubMed:19561640"
FT MUTAGEN 1301
FT /note="Y->A: No effect on interaction with WWOX. Abolishes
FT interaction with WWOX; when associated with A-1035. Loss of
FT interaction with YAP1 and stimulation of transcription."
FT /evidence="ECO:0000269|PubMed:12807903,
FT ECO:0000269|PubMed:16061658, ECO:0000269|PubMed:19561640"
FT MUTAGEN 1301
FT /note="Y->F: Abolishes interaction with WWP1; when
FT associated with F-1056."
FT /evidence="ECO:0000269|PubMed:12807903,
FT ECO:0000269|PubMed:16061658, ECO:0000269|PubMed:19561640"
FT STRAND 28..30
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 38..41
FT /evidence="ECO:0007829|PDB:3U7U"
FT HELIX 42..53
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 57..61
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 63..67
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 75..79
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 82..85
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 87..91
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 95..98
FT /evidence="ECO:0007829|PDB:2AHX"
FT TURN 112..114
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 115..120
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 125..128
FT /evidence="ECO:0007829|PDB:3U2P"
FT STRAND 133..135
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 144..150
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 158..160
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 163..165
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 173..175
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 176..178
FT /evidence="ECO:0007829|PDB:2AHX"
FT TURN 191..193
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 197..201
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 202..204
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 221..225
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 226..228
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 234..242
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 245..254
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 257..261
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 265..269
FT /evidence="ECO:0007829|PDB:2AHX"
FT TURN 270..273
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 274..277
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 288..292
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 298..300
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 303..307
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 312..317
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 320..325
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 327..329
FT /evidence="ECO:0007829|PDB:3U2P"
FT STRAND 333..335
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 340..342
FT /evidence="ECO:0007829|PDB:2AHX"
FT TURN 350..352
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 353..356
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 360..364
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 366..368
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 370..374
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 377..379
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 386..394
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 397..400
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 402..405
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 415..417
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 432..438
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 455..461
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 469..471
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 474..476
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 479..482
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 485..487
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 489..491
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 493..497
FT /evidence="ECO:0007829|PDB:2AHX"
FT TURN 498..500
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 512..516
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 519..528
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 531..534
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 537..543
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 545..548
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 551..554
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 568..573
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 576..585
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 588..592
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 595..608
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 612..616
FT /evidence="ECO:0007829|PDB:2AHX"
FT STRAND 625..629
FT /evidence="ECO:0007829|PDB:2AHX"
FT HELIX 651..676
FT /evidence="ECO:0007829|PDB:2L2T"
FT HELIX 715..717
FT /evidence="ECO:0007829|PDB:2R4B"
FT STRAND 718..729
FT /evidence="ECO:0007829|PDB:2R4B"
FT STRAND 731..737
FT /evidence="ECO:0007829|PDB:2R4B"
FT STRAND 740..743
FT /evidence="ECO:0007829|PDB:3BBT"
FT STRAND 746..752
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 762..773
FT /evidence="ECO:0007829|PDB:2R4B"
FT STRAND 778..780
FT /evidence="ECO:0007829|PDB:3BBT"
FT STRAND 783..787
FT /evidence="ECO:0007829|PDB:2R4B"
FT STRAND 789..791
FT /evidence="ECO:0007829|PDB:2R4B"
FT STRAND 793..797
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 804..810
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 812..814
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 817..836
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 846..848
FT /evidence="ECO:0007829|PDB:2R4B"
FT STRAND 849..853
FT /evidence="ECO:0007829|PDB:2R4B"
FT STRAND 856..859
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 864..869
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 884..886
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 889..893
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 899..914
FT /evidence="ECO:0007829|PDB:2R4B"
FT TURN 920..923
FT /evidence="ECO:0007829|PDB:2R4B"
FT TURN 926..928
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 929..934
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 947..955
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 961..963
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 967..977
FT /evidence="ECO:0007829|PDB:2R4B"
FT HELIX 981..983
FT /evidence="ECO:0007829|PDB:2R4B"
SQ SEQUENCE 1308 AA; 146808 MW; 5E4AE80985D88761 CRC64;
MKPATGLWVW VSLLVAAGTV QPSDSQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM
GNLEITSIEH NRDLSFLRSV REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF
LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNLTLVST
NGSSGCGRCH KSCTGRCWGP TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG
PKDTDCFACM NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD
SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS SNIDKFINCT
KINGNLIFLV TGIHGDPYNA IEAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL
VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST
INQRIVIRDN RKAENCTAEG MVCNHLCSSD GCWGPGPDQC LSCRRFSRGR ICIESCNLYD
GEFREFENGS ICVECDPQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA
NSFIFKYADP DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG
LFILVIVGLT FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR
VKVLGSGAFG TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASMDHPHL
VRLLGVCLSP TIQLVTQLMP HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV
HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ
SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY MVMVKCWMID
ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE
EYLVPQAFNI PPPIYTSRAR IDSNRSEIGH SPPPAYTPMS GNQFVYRDGG FAAEQGVSVP
YRAPTSTIPE APVAQGATAE IFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERS
PRGELDEEGY MTPMRDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHN ASNGPPKAED
EYVNEPLYLN TFANTLGKAE YLKNNILSMP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ
EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTVLPPPP YRHRNTVV
