ID ERBB4_MOUSE Reviewed; 1308 AA. AC Q61527; B2KGF5; B2KGF6; O88460; Q3UNS6; DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot. DT 25-JAN-2012, sequence version 5. DT 27-MAR-2024, entry version 202. 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 Contains: DE RecName: Full=ERBB4 intracellular domain; DE Short=4ICD; DE Short=E4ICD; DE AltName: Full=s80HER4; DE Flags: Precursor; GN Name=Erbb4; Synonyms=Mer4; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1263 (JM-A CYT-2). RC STRAIN=C57BL/6J; TISSUE=Kidney; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] OF 624-650 (ISOFORMS JM-A CYT-2 AND JM-B CYT-2). RC TISSUE=Heart, and Kidney; 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 [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1019-1102 (ISOFORM JM-A CYT-1). RC STRAIN=C57BL/6J; TISSUE=Brain; RX PubMed=7589796; DOI=10.1006/dbio.1995.0012; RA Moscoso L.M., Chu G.C., Gautam M., Noakes P.G., Merlie J.P., Sanes J.R.; RT "Synapse-associated expression of an acetylcholine receptor-inducing RT protein, ARIA/heregulin, and its putative receptors, ErbB2 and ErbB3, in RT developing mammalian muscle."; RL Dev. Biol. 172:158-169(1995). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1019-1093 (ISOFORM JM-A CYT-1). RC STRAIN=CD-1; TISSUE=Uterus; RA Lim H., Das S.K., Dey S.K.; RT "Potential signaling network by EGF-like growth factors in the mouse uterus RT during early pregnancy."; RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases. RN [6] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=7477376; DOI=10.1038/378390a0; RA Gassmann M., Casagranda F., Orioli D., Simon H., Lai C., Klein R., RA Lemke G.; RT "Aberrant neural and cardiac development in mice lacking the ErbB4 RT neuregulin receptor."; RL Nature 378:390-394(1995). RN [7] RP FUNCTION IN MAMMARY GLAND DEVELOPMENT AND ACTIVATION OF STAT5A, AND RP INTERACTION WITH STAT5A. RX PubMed=10508857; DOI=10.1083/jcb.147.1.77; RA Jones F.E., Welte T., Fu X.Y., Stern D.F.; RT "ErbB4 signaling in the mammary gland is required for lobuloalveolar RT development and Stat5 activation during lactation."; RL J. Cell Biol. 147:77-88(1999). RN [8] RP ALTERNATIVE SPLICING, AND TISSUE 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 [9] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=10655590; DOI=10.1038/35000058; RA Golding J.P., Trainor P., Krumlauf R., Gassmann M.; RT "Defects in pathfinding by cranial neural crest cells in mice lacking the RT neuregulin receptor ErbB4."; RL Nat. Cell Biol. 2:103-109(2000). RN [10] RP DISRUPTION PHENOTYPE. RX PubMed=12954715; DOI=10.1242/dev.00715; RA Long W., Wagner K.U., Lloyd K.C., Binart N., Shillingford J.M., RA Hennighausen L., Jones F.E.; RT "Impaired differentiation and lactational failure of Erbb4-deficient RT mammary glands identify ERBB4 as an obligate mediator of STAT5."; RL Development 130:5257-5268(2003). RN [11] RP DISRUPTION PHENOTYPE. RX PubMed=12824469; DOI=10.1073/pnas.1436402100; RA Tidcombe H., Jackson-Fisher A., Mathers K., Stern D.F., Gassmann M., RA Golding J.P.; RT "Neural and mammary gland defects in ErbB4 knockout mice genetically RT rescued from embryonic lethality."; RL Proc. Natl. Acad. Sci. U.S.A. 100:8281-8286(2003). RN [12] RP FUNCTION IN NEUROBLAST MIGRATION. RX PubMed=15543145; DOI=10.1038/nn1345; RA Anton E.S., Ghashghaei H.T., Weber J.L., McCann C., Fischer T.M., RA Cheung I.D., Gassmann M., Messing A., Klein R., Schwab M.H., Lloyd K.C., RA Lai C.; RT "Receptor tyrosine kinase ErbB4 modulates neuroblast migration and RT placement in the adult forebrain."; RL Nat. Neurosci. 7:1319-1328(2004). RN [13] RP FUNCTION. RX PubMed=15863494; DOI=10.1074/jbc.m414044200; RA Clark D.E., Williams C.C., Duplessis T.T., Moring K.L., Notwick A.R., RA Long W., Lane W.S., Beuvink I., Hynes N.E., Jones F.E.; RT "ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel RT STAT5A serine phosphorylation events."; RL J. Biol. Chem. 280:24175-24180(2005). RN [14] 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 [15] RP FUNCTION, PROTEOLYTIC PROCESSING, AND SUBCELLULAR LOCATION. 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 [16] RP FUNCTION OF E4ICD. RX PubMed=19596786; DOI=10.1128/mcb.01705-08; RA Muraoka-Cook R.S., Sandahl M.A., Strunk K.E., Miraglia L.C., Husted C., RA Hunter D.M., Elenius K., Chodosh L.A., Earp H.S. III; RT "ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert RT opposing effects on the mammary epithelium in vivo."; RL Mol. Cell. Biol. 29:4935-4948(2009). RN [17] RP FUNCTION AS NRG1 RECEPTOR IN POSTNATAL CARDIOMYOCYTE PROLIFERATION. RX PubMed=19632177; DOI=10.1016/j.cell.2009.04.060; RA Bersell K., Arab S., Haring B., Kuhn B.; RT "Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair RT of heart injury."; RL Cell 138:257-270(2009). RN [18] RP REVIEW. 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 [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [20] RP REVIEW ON ROLE AS NEUREGULIN RECEPTOR. RX PubMed=21295966; DOI=10.1016/j.gde.2010.12.010; RA Rico B., Marin O.; RT "Neuregulin signaling, cortical circuitry development and schizophrenia."; RL Curr. Opin. Genet. Dev. 21:262-270(2011). 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:10508857, CC ECO:0000269|PubMed:10655590, ECO:0000269|PubMed:15543145, CC ECO:0000269|PubMed:15863494, ECO:0000269|PubMed:16837552, CC ECO:0000269|PubMed:19596786, ECO:0000269|PubMed:19632177, CC ECO:0000269|PubMed:7477376}. 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 -!- 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+) (By similarity). {ECO:0000250}. 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 DLG2 (via its PDZ domain), DLG3 (via its PDZ domain), DLG4 (via its PDZ CC domain) and SNTB2 (via its PDZ domain). Interacts with MUC1. Interacts CC (via its PPxy motifs) with WWOX. Interacts (via the PPxY motif 3 of CC isoform JM-A CYT-2) with YAP1 (via the WW domain 1 of isoform 1). CC Interacts (isoform JM-A CYT-1 and isoform JM-B CYT-1) with WWP1. CC Interacts (via its intracellular domain) with TRIM28. Interacts (via CC the intracellular domains of both CYT-1 and CYT-2 isoforms) with KAP1; CC the interaction does not phosphorylate KAP1 but represses ERBB4- CC mediated transcriptional activity. Interacts with PRPU, DDX23, MATR3, CC RBM15, ILF3, KAP1, U5S1, U2SURP, ITCH, HNRNPU, AP2A1, NULC, LEO1, WWP2, CC IGHG1, HXK1, GRB7 and SRRT. Interacts (phosphorylated isoform JM-A CYT- CC 1 and isoform JM-B CYT-1) with PIK3R1. Interacts with SHC1. Interacts CC with GRB2. Interacts (soluble intracellular domain) with BCL2. CC Interacts (phosphorylated) with STAT1 (By similarity). Interacts with CC CBFA2T3. Interacts (soluble intracellular domain) with STAT5A. CC {ECO:0000250, ECO:0000269|PubMed:10508857, CC ECO:0000269|PubMed:16815842}. CC -!- INTERACTION: CC Q61527; Q9NZC7: WWOX; Xeno; NbExp=3; IntAct=EBI-4398741, EBI-4320739; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16837552}; CC Single-pass type I membrane protein {ECO:0000269|PubMed:16837552}. CC Note=In response to NRG1 treatment, the activated receptor is CC internalized. CC -!- SUBCELLULAR LOCATION: [ERBB4 intracellular domain]: Nucleus. CC Mitochondrion {ECO:0000250}. 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 (By CC similarity). {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Comment=Additional isoforms seem to exist.; CC Name=JM-A CYT-1; CC IsoId=Q61527-1; Sequence=Displayed; CC Name=JM-B CYT-2; CC IsoId=Q61527-2; Sequence=VSP_002896; CC Name=JM-A CYT-2; CC IsoId=Q61527-3; Sequence=VSP_042131; CC -!- TISSUE SPECIFICITY: Isoform JM-A CYT-2 and isoform JM-B CYT-2 are CC expressed in cerebellum, cerebral cortex, spinal cord, medulla CC oblongata and eye, but the kidney expresses solely isoform JM-A CYT-2 CC and the heart solely isoform JM-B CYT-2. {ECO:0000269|PubMed:10353604}. 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 (By similarity). {ECO:0000250}. 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 (By CC similarity). {ECO:0000250}. 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 (By similarity). {ECO:0000250}. CC -!- DISRUPTION PHENOTYPE: Embryonically lethal. Embryos die at about 10 CC dpc, due to defects in the development of myocardial trabeculae in the CC heart ventricle that lead to severely reduced embryonic blood flow. CC Mice also display aberrant innervation from and to the hindbrain, CC especially concerning the trigeminal, facial and acoustic ganglia. This CC is due to aberrant migration of a subpopulation of cranial neural crest CC cells. {ECO:0000269|PubMed:10655590, ECO:0000269|PubMed:12824469, CC ECO:0000269|PubMed:12954715, ECO:0000269|PubMed:7477376}. 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 --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; CU368746; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CU372923; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CU392849; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CU405881; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CU407006; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CU459008; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CU459207; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AK144050; BAE25671.1; -; mRNA. DR EMBL; L47241; AAA93534.1; -; mRNA. DR EMBL; AF059177; AAC28334.1; -; mRNA. DR CCDS; CCDS48285.1; -. [Q61527-3] DR RefSeq; NP_034284.1; NM_010154.2. [Q61527-3] DR RefSeq; XP_006495755.1; XM_006495692.3. [Q61527-1] DR RefSeq; XP_006495756.1; XM_006495693.3. [Q61527-2] DR AlphaFoldDB; Q61527; -. DR SMR; Q61527; -. DR BioGRID; 199498; 7. DR DIP; DIP-29887N; -. DR IntAct; Q61527; 3. DR STRING; 10090.ENSMUSP00000114123; -. DR GlyConnect; 2677; 1 N-Linked glycan (1 site). DR GlyCosmos; Q61527; 11 sites, 1 glycan. DR GlyGen; Q61527; 11 sites, 1 N-linked glycan (1 site). DR iPTMnet; Q61527; -. DR PhosphoSitePlus; Q61527; -. DR SwissPalm; Q61527; -. DR jPOST; Q61527; -. DR MaxQB; Q61527; -. DR PaxDb; 10090-ENSMUSP00000114123; -. DR PeptideAtlas; Q61527; -. DR ProteomicsDB; 275879; -. [Q61527-1] DR ProteomicsDB; 275880; -. [Q61527-2] DR ProteomicsDB; 275881; -. [Q61527-3] DR Antibodypedia; 1602; 1605 antibodies from 46 providers. DR DNASU; 13869; -. DR Ensembl; ENSMUST00000119142.8; ENSMUSP00000112713.2; ENSMUSG00000062209.16. [Q61527-1] DR Ensembl; ENSMUST00000121473.8; ENSMUSP00000114123.2; ENSMUSG00000062209.16. [Q61527-3] DR GeneID; 13869; -. DR KEGG; mmu:13869; -. DR UCSC; uc007bjb.1; mouse. [Q61527-3] DR AGR; MGI:104771; -. DR CTD; 2066; -. DR MGI; MGI:104771; Erbb4. DR VEuPathDB; HostDB:ENSMUSG00000062209; -. DR eggNOG; KOG1025; Eukaryota. DR GeneTree; ENSGT00940000154695; -. DR HOGENOM; CLU_003384_1_1_1; -. DR InParanoid; Q61527; -. DR OMA; HAXLVEP; -. DR OrthoDB; 1614410at2759; -. DR PhylomeDB; Q61527; -. DR TreeFam; TF106002; -. DR Reactome; R-MMU-1227986; Signaling by ERBB2. DR Reactome; R-MMU-1236394; Signaling by ERBB4. DR Reactome; R-MMU-1250196; SHC1 events in ERBB2 signaling. DR Reactome; R-MMU-1250342; PI3K events in ERBB4 signaling. DR Reactome; R-MMU-1250347; SHC1 events in ERBB4 signaling. DR Reactome; R-MMU-1251985; Nuclear signaling by ERBB4. DR Reactome; R-MMU-1253288; Downregulation of ERBB4 signaling. DR Reactome; R-MMU-1257604; PIP3 activates AKT signaling. DR Reactome; R-MMU-1963640; GRB2 events in ERBB2 signaling. DR Reactome; R-MMU-1963642; PI3K events in ERBB2 signaling. DR Reactome; R-MMU-5673001; RAF/MAP kinase cascade. DR Reactome; R-MMU-6785631; ERBB2 Regulates Cell Motility. DR Reactome; R-MMU-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR Reactome; R-MMU-8847993; ERBB2 Activates PTK6 Signaling. DR Reactome; R-MMU-8863795; Downregulation of ERBB2 signaling. DR Reactome; R-MMU-9018519; Estrogen-dependent gene expression. DR BioGRID-ORCS; 13869; 1 hit in 82 CRISPR screens. DR ChiTaRS; Erbb4; mouse. DR PRO; PR:Q61527; -. DR Proteomes; UP000000589; Chromosome 1. DR RNAct; Q61527; Protein. DR Bgee; ENSMUSG00000062209; Expressed in neural tube mantle layer and 155 other cell types or tissues. DR ExpressionAtlas; Q61527; baseline and differential. DR GO; GO:0009925; C:basal plasma membrane; IBA:GO_Central. DR GO; GO:0016323; C:basolateral plasma membrane; ISO:MGI. DR GO; GO:0005901; C:caveola; ISO:MGI. DR GO; GO:0030425; C:dendrite; ISO:MGI. DR GO; GO:0098982; C:GABA-ergic synapse; IDA:SynGO. DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO. DR GO; GO:0005739; C:mitochondrion; ISO:MGI. DR GO; GO:0031594; C:neuromuscular junction; IDA:SynGO. DR GO; GO:0043025; C:neuronal cell body; ISO:MGI. DR GO; GO:0005634; C:nucleus; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; IDA:MGI. DR GO; GO:0098839; C:postsynaptic density membrane; IDA:MGI. DR GO; GO:0045211; C:postsynaptic membrane; ISS:UniProtKB. DR GO; GO:0042734; C:presynaptic membrane; IDA:SynGO. DR GO; GO:0043235; C:receptor complex; ISO:MGI. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0005006; F:epidermal growth factor receptor activity; IGI:MGI. DR GO; GO:0005154; F:epidermal growth factor receptor binding; ISO:MGI. DR GO; GO:0050811; F:GABA receptor binding; IDA:MGI. DR GO; GO:0038132; F:neuregulin binding; ISO:MGI. DR GO; GO:0038131; F:neuregulin receptor activity; IDA:MGI. DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI. DR GO; GO:0004713; F:protein tyrosine kinase activity; ISO:MGI. DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:MGI. DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:MGI. DR GO; GO:0061026; P:cardiac muscle tissue regeneration; IMP:UniProtKB. DR GO; GO:0045165; P:cell fate commitment; IDA:MGI. DR GO; GO:0016477; P:cell migration; ISS:UniProtKB. DR GO; GO:0007166; P:cell surface receptor signaling pathway; IDA:MGI. DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IDA:MGI. DR GO; GO:0021551; P:central nervous system morphogenesis; IMP:UniProtKB. DR GO; GO:0009880; P:embryonic pattern specification; IMP:UniProtKB. DR GO; GO:0038135; P:ERBB2-ERBB4 signaling pathway; IDA:MGI. DR GO; GO:0038130; P:ERBB4 signaling pathway; IMP: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; IMP:MGI. DR GO; GO:0007507; P:heart development; IMP:MGI. DR GO; GO:0007595; P:lactation; IMP:UniProtKB. DR GO; GO:0060749; P:mammary gland alveolus development; IMP:UniProtKB. DR GO; GO:0060644; P:mammary gland epithelial cell differentiation; IMP:UniProtKB. DR GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; ISS:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB. DR GO; GO:0010656; P:negative regulation of muscle cell apoptotic process; ISO:MGI. DR GO; GO:0007399; P:nervous system development; IMP:MGI. DR GO; GO:0001755; P:neural crest cell migration; IMP:UniProtKB. DR GO; GO:0022008; P:neurogenesis; IBA:GO_Central. DR GO; GO:0099645; P:neurotransmitter receptor localization to postsynaptic specialization membrane; IDA:SynGO. DR GO; GO:0021889; P:olfactory bulb interneuron differentiation; IMP:UniProtKB. DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISS:UniProtKB. DR GO; GO:0060045; P:positive regulation of cardiac muscle cell proliferation; IMP:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; ISO:MGI. DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:UniProtKB. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISO:MGI. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB. DR GO; GO:0046326; P:positive regulation of glucose import; ISO:MGI. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IGI:MGI. DR GO; GO:0071073; P:positive regulation of phospholipid biosynthetic process; ISO:MGI. DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IGI:MGI. DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; IMP:UniProtKB. DR GO; GO:0032230; P:positive regulation of synaptic transmission, GABAergic; ISO:MGI. DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IMP:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB. DR GO; GO:0007259; P:receptor signaling pathway via JAK-STAT; IMP:UniProtKB. DR GO; GO:0030334; P:regulation of cell migration; IMP:UniProtKB. DR GO; GO:0007165; P:signal transduction; ISO:MGI. DR GO; GO:0043129; P:surfactant homeostasis; ISO:MGI. DR GO; GO:0007416; P:synapse assembly; IDA:SynGO. DR GO; GO:0060074; P:synapse maturation; ISO:MGI. DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; ISS:UniProtKB. DR CDD; cd00064; FU; 3. DR CDD; cd05110; PTKc_HER4; 1. DR CDD; cd12092; TM_ErbB4; 1. DR Gene3D; 6.10.250.880; -; 1. DR Gene3D; 3.80.20.20; Receptor L-domain; 2. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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; IPR049328; TM_ErbB1. DR InterPro; IPR008266; Tyr_kinase_AS. DR InterPro; IPR020635; Tyr_kinase_cat_dom. DR InterPro; IPR016245; Tyr_kinase_EGF/ERB/XmrK_rcpt. DR PANTHER; PTHR24416:SF90; RECEPTOR TYROSINE-PROTEIN KINASE ERBB-4; 1. DR PANTHER; PTHR24416; TYROSINE-PROTEIN KINASE RECEPTOR; 1. 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 Pfam; PF21314; TM_ErbB1; 1. DR PIRSF; PIRSF000619; TyrPK_EGF-R; 1. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00261; FU; 5. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF57184; Growth factor receptor domain; 2. DR SUPFAM; SSF52058; L domain-like; 2. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. DR Genevisible; Q61527; MM. PE 1: Evidence at protein level; KW Activator; Alternative splicing; Apoptosis; ATP-binding; Cell membrane; KW Developmental protein; Disulfide bond; Glycoprotein; Kinase; Lactation; KW Membrane; Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein; KW Receptor; Reference proteome; Repeat; Signal; Transcription; KW Transcription regulation; Transferase; Transmembrane; Transmembrane helix; KW Tyrosine-protein kinase; 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_0000270146" FT CHAIN 676..1308 FT /note="ERBB4 intracellular domain" FT /id="PRO_0000396798" FT TOPO_DOM 26..652 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 653..673 FT /evidence="ECO:0000255" FT TOPO_DOM 674..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..1149 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 676..684 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250" FT MOTIF 1032..1035 FT /note="PPxy motif 1" FT /evidence="ECO:0000250" FT MOTIF 1282..1285 FT /note="PPxY motif 2" FT /evidence="ECO:0000250" FT MOTIF 1290..1292 FT /note="PDZ-binding" FT /evidence="ECO:0000250" 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:0000250|UniProtKB:Q15303" FT MOD_RES 1035 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q15303" FT MOD_RES 1056 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q15303" FT MOD_RES 1150 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q15303" FT MOD_RES 1162 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q15303" FT MOD_RES 1188 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q15303" FT MOD_RES 1202 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q15303" FT MOD_RES 1242 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q15303" FT MOD_RES 1258 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q15303" FT MOD_RES 1284 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:Q15303" FT CARBOHYD 138 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 174 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" 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:0000255" FT CARBOHYD 410 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 473 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 495 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" 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:0000255" FT CARBOHYD 620 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 29..56 FT /evidence="ECO:0000250" FT DISULFID 156..186 FT /evidence="ECO:0000250" FT DISULFID 189..197 FT /evidence="ECO:0000250" FT DISULFID 193..205 FT /evidence="ECO:0000250" FT DISULFID 213..221 FT /evidence="ECO:0000250" FT DISULFID 217..229 FT /evidence="ECO:0000250" FT DISULFID 230..238 FT /evidence="ECO:0000250" FT DISULFID 234..246 FT /evidence="ECO:0000250" FT DISULFID 249..258 FT /evidence="ECO:0000250" FT DISULFID 262..289 FT /evidence="ECO:0000250" FT DISULFID 293..304 FT /evidence="ECO:0000250" FT DISULFID 308..323 FT /evidence="ECO:0000250" FT DISULFID 326..330 FT /evidence="ECO:0000250" FT DISULFID 503..512 FT /evidence="ECO:0000250" FT DISULFID 507..520 FT /evidence="ECO:0000250" FT DISULFID 523..532 FT /evidence="ECO:0000250" FT DISULFID 536..552 FT /evidence="ECO:0000250" FT DISULFID 555..569 FT /evidence="ECO:0000250" FT DISULFID 559..577 FT /evidence="ECO:0000250" FT DISULFID 580..589 FT /evidence="ECO:0000250" FT DISULFID 593..614 FT /evidence="ECO:0000250" FT DISULFID 617..625 FT /evidence="ECO:0000250" FT DISULFID 621..633 FT /evidence="ECO:0000250" FT VAR_SEQ 626..648 FT /note="NGPTSHDCIYYPWTGHSTLPQHA -> IGSSIEDCIGLTD (in isoform FT JM-BCYT-2)" FT /evidence="ECO:0000303|PubMed:9334263" FT /id="VSP_002896" FT VAR_SEQ 1046..1061 FT /note="Missing (in isoform JM-ACYT-2)" FT /evidence="ECO:0000303|PubMed:9334263" FT /id="VSP_042131" FT CONFLICT 1019 FT /note="A -> V (in Ref. 5; AAC28334)" FT /evidence="ECO:0000305" SQ SEQUENCE 1308 AA; 146855 MW; 65943278A7E7F2F6 CRC64; MKLATGLWVW GSLLMAAGTV QPSASQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM GNLEITSIEH NRDLSFLRSI REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNMTLVST NGSSGCGRCH KSCTGRCWGP TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG PKDTDCFACM NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS SNIDKFINCT KINGNLIFLV TGIHGDPYNA IDAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST INQRIVIRDN RRAENCTAEG MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD GEFREFENGS ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA NSFIFKYADQ DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG LFILVIMALT FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR VKVLGSGAFG TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASMDHPHL VRLLGVCLSP TIQLVTQLMP HGCLLDYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY MVMVKCWMID ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE EYLVPQAFNI PPPIYTSRTR IDSNRSEIGH SPPPAYTPMS GNQFVYQDGG FATQQGMPMP YRATTSTIPE APVAQGATAE MFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERN PRGELDEEGY MTPMHDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHS ASSGPPKAED EYVNEPLYLN TFANALGSAE YMKNSVLSVP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTMLPPPP YRHRNTVV //