ERBB4_RAT
ID ERBB4_RAT Reviewed; 1308 AA.
AC Q62956; Q6UA28; Q6UA29; Q9Z2N7;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 06-JUN-2002, sequence version 3.
DT 03-AUG-2022, entry version 191.
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=Tyro-2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM JM-A CYT1).
RC TISSUE=Heart;
RX PubMed=9553078; DOI=10.1074/jbc.273.17.10261;
RA Zhao Y.-Y., Sawyer D.R., Baliga R.R., Opel D.J., Han X., Marchionni M.A.,
RA Kelly R.A.;
RT "Neuregulins promote survival and growth of cardiac myocytes. Persistence
RT of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes.";
RL J. Biol. Chem. 273:10261-10269(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS JM-A CYT1 AND JM-A CYT2).
RC STRAIN=Wistar; TISSUE=Olfactory bulb;
RX PubMed=15355992; DOI=10.1074/jbc.m408374200;
RA Gambarotta G., Garzotto D., Destro E., Mautino B., Giampietro C.,
RA Cutrupi S., Dati C., Cattaneo E., Fasolo A., Perroteau I.;
RT "ErbB4 expression in neural progenitor cells (ST14A) is necessary to
RT mediate neuregulin-1-beta1-induced migration.";
RL J. Biol. Chem. 279:48808-48816(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 848-901.
RC TISSUE=Sciatic nerve;
RX PubMed=2025425; DOI=10.1016/0896-6273(91)90167-x;
RA Lai C., Lemke G.;
RT "An extended family of protein-tyrosine kinase genes differentially
RT expressed in the vertebrate nervous system.";
RL Neuron 6:691-704(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1031-1198.
RC STRAIN=Sprague-Dawley; TISSUE=Spinal cord;
RX PubMed=9030624; DOI=10.1523/jneurosci.17-05-01642.1997;
RA Carroll S.L., Miller M.L., Frohnert P.W., Kim S.S., Corbett J.A.;
RT "Expression of neuregulins and their putative receptors, ErbB2 and ErbB3,
RT is induced during Wallerian degeneration.";
RL J. Neurosci. 17:1642-1659(1997).
RN [5]
RP FUNCTION.
RX PubMed=10839362; DOI=10.1016/s0896-6273(00)81176-9;
RA Huang Y.Z., Won S., Ali D.W., Wang Q., Tanowitz M., Du Q.S., Pelkey K.A.,
RA Yang D.J., Xiong W.C., Salter M.W., Mei L.;
RT "Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS
RT synapses.";
RL Neuron 26:443-455(2000).
RN [6]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=14654373; DOI=10.1016/j.yjmcc.2003.09.012;
RA Fukazawa R., Miller T.A., Kuramochi Y., Frantz S., Kim Y.D.,
RA Marchionni M.A., Kelly R.A., Sawyer D.B.;
RT "Neuregulin-1 protects ventricular myocytes from anthracycline-induced
RT apoptosis via erbB4-dependent activation of PI3-kinase/Akt.";
RL J. Mol. Cell. Cardiol. 35:1473-1479(2003).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=12716924; DOI=10.1523/jneurosci.23-08-03164.2003;
RA Ma L., Huang Y.Z., Pitcher G.M., Valtschanoff J.G., Ma Y.H., Feng L.Y.,
RA Lu B., Xiong W.C., Salter M.W., Weinberg R.J., Mei L.;
RT "Ligand-dependent recruitment of the ErbB4 signaling complex into neuronal
RT lipid rafts.";
RL J. Neurosci. 23:3164-3175(2003).
RN [8]
RP FUNCTION AS NRG1 RECEPTOR IN ACTIVATION OF AKT1 AND THE MAP KINASES
RP MAPK1/ERK2 AND/OR MAPK3/ERK1, AND SUBCELLULAR LOCATION.
RX PubMed=17250808; DOI=10.1016/j.bbrc.2007.01.009;
RA Liu Y., Tao Y.M., Woo R.S., Xiong W.C., Mei L.;
RT "Stimulated ErbB4 internalization is necessary for neuregulin signaling in
RT neurons.";
RL Biochem. Biophys. Res. Commun. 354:505-510(2007).
RN [9]
RP FUNCTION.
RX PubMed=17521571; DOI=10.1016/j.neuron.2007.03.028;
RA Li B., Woo R.S., Mei L., Malinow R.;
RT "The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation
RT and plasticity.";
RL Neuron 54:583-597(2007).
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:10839362,
CC ECO:0000269|PubMed:12716924, ECO:0000269|PubMed:14654373,
CC ECO:0000269|PubMed:17250808, ECO:0000269|PubMed:17521571}.
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 (By
CC similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:12716924,
CC ECO:0000269|PubMed:17250808}; Single-pass type I membrane protein
CC {ECO:0000269|PubMed:12716924, ECO:0000269|PubMed:17250808}. Note=In
CC response to NRG1 treatment, the activated receptor is internalized.
CC -!- SUBCELLULAR LOCATION: [ERBB4 intracellular domain]: Nucleus
CC {ECO:0000250}. Mitochondrion {ECO:0000250}. Note=Following
CC proteolytical processing E4ICD (E4ICD1 or E4ICD2 generated from the
CC respective isoforms) is translocated to the nucleus. Significantly more
CC E4ICD2 than E4ICD1 is found in the nucleus. E4ICD2 derived from
CC processing of isoform JM-A CYT-2 colocalizes with YAP1 in the nucleus
CC (By similarity). {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Comment=Additional isoforms seem to exist.;
CC Name=JM-A CYT1; Synonyms=JMa cyt1;
CC IsoId=Q62956-1; Sequence=Displayed;
CC Name=JM-A CYT2; Synonyms=JMa cyt2;
CC IsoId=Q62956-2; Sequence=VSP_022150;
CC -!- TISSUE SPECIFICITY: Preferentially expressed in the developing nervous
CC system. Exhibits distinct and highly regionalized patterns of
CC expression in the adult brain, where it is mainly found in the
CC reticular nucleus of the thalamus. Very low levels in kidney, and
CC heart.
CC -!- PTM: Isoform JM-A CYT-2 and isoform JM-A CYT-1 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, which are further processed by a presenilin-dependent
CC gamma-secretase to release the respective cytoplasmic intracellular
CC domain E4ICD (either E4ICD1/s80Cyt1 or E4ICD2/s80Cyt2) (By similarity).
CC {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 -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. EGF receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; AF041838; AAD08899.1; -; mRNA.
DR EMBL; AY375306; AAQ77348.1; -; mRNA.
DR EMBL; AY375307; AAQ77349.1; -; mRNA.
DR EMBL; U52531; AAC53051.1; -; mRNA.
DR PIR; PT0184; PT0184.
DR RefSeq; NP_067719.1; NM_021687.1. [Q62956-1]
DR AlphaFoldDB; Q62956; -.
DR SMR; Q62956; -.
DR BioGRID; 248766; 4.
DR STRING; 10116.ENSRNOP00000019283; -.
DR GlyGen; Q62956; 10 sites.
DR iPTMnet; Q62956; -.
DR PhosphoSitePlus; Q62956; -.
DR SwissPalm; Q62956; -.
DR PaxDb; Q62956; -.
DR PRIDE; Q62956; -.
DR GeneID; 59323; -.
DR KEGG; rno:59323; -.
DR UCSC; RGD:620486; rat. [Q62956-1]
DR CTD; 2066; -.
DR RGD; 620486; Erbb4.
DR eggNOG; KOG1025; Eukaryota.
DR InParanoid; Q62956; -.
DR OrthoDB; 81952at2759; -.
DR PhylomeDB; Q62956; -.
DR BRENDA; 2.7.10.1; 5301.
DR Reactome; R-RNO-1227986; Signaling by ERBB2. [Q62956-1]
DR Reactome; R-RNO-1236394; Signaling by ERBB4. [Q62956-1]
DR Reactome; R-RNO-1250196; SHC1 events in ERBB2 signaling. [Q62956-1]
DR Reactome; R-RNO-1250342; PI3K events in ERBB4 signaling. [Q62956-1]
DR Reactome; R-RNO-1250347; SHC1 events in ERBB4 signaling. [Q62956-1]
DR Reactome; R-RNO-1251985; Nuclear signaling by ERBB4. [Q62956-1]
DR Reactome; R-RNO-1253288; Downregulation of ERBB4 signaling. [Q62956-1]
DR Reactome; R-RNO-1257604; PIP3 activates AKT signaling. [Q62956-1]
DR Reactome; R-RNO-1963640; GRB2 events in ERBB2 signaling. [Q62956-1]
DR Reactome; R-RNO-1963642; PI3K events in ERBB2 signaling. [Q62956-1]
DR Reactome; R-RNO-5673001; RAF/MAP kinase cascade. [Q62956-1]
DR Reactome; R-RNO-6785631; ERBB2 Regulates Cell Motility. [Q62956-1]
DR Reactome; R-RNO-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. [Q62956-1]
DR Reactome; R-RNO-8847993; ERBB2 Activates PTK6 Signaling. [Q62956-1]
DR Reactome; R-RNO-8863795; Downregulation of ERBB2 signaling. [Q62956-1]
DR Reactome; R-RNO-9018519; Estrogen-dependent gene expression. [Q62956-1]
DR PRO; PR:Q62956; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0009925; C:basal plasma membrane; IBA:GO_Central.
DR GO; GO:0016323; C:basolateral plasma membrane; ISO:RGD.
DR GO; GO:0005901; C:caveola; IDA:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0030425; C:dendrite; IDA:RGD.
DR GO; GO:0005615; C:extracellular space; ISO:RGD.
DR GO; GO:0098982; C:GABA-ergic synapse; ISO:RGD.
DR GO; GO:0098978; C:glutamatergic synapse; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0099061; C:integral component of postsynaptic density membrane; ISO:RGD.
DR GO; GO:0099056; C:integral component of presynaptic membrane; ISO:RGD.
DR GO; GO:0045121; C:membrane raft; IDA:RGD.
DR GO; GO:0005739; C:mitochondrion; ISO:RGD.
DR GO; GO:0043025; C:neuronal cell body; IDA:RGD.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0014069; C:postsynaptic density; IDA:RGD.
DR GO; GO:0098839; C:postsynaptic density membrane; ISO:RGD.
DR GO; GO:0045211; C:postsynaptic membrane; IDA:UniProtKB.
DR GO; GO:0043235; C:receptor complex; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; ISO:RGD.
DR GO; GO:0050811; F:GABA receptor binding; ISO:RGD.
DR GO; GO:0038131; F:neuregulin receptor activity; IDA:MGI.
DR GO; GO:0046983; F:protein dimerization activity; ISO:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0030296; F:protein tyrosine kinase activator activity; ISO:RGD.
DR GO; GO:0004713; F:protein tyrosine kinase activity; ISO:RGD.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISO:RGD.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; ISS:UniProtKB.
DR GO; GO:0061026; P:cardiac muscle tissue regeneration; ISS:UniProtKB.
DR GO; GO:0045165; P:cell fate commitment; ISO:RGD.
DR GO; GO:0016477; P:cell migration; ISS:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; ISO:RGD.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0038130; P:ERBB4 signaling pathway; IDA:MGI.
DR GO; GO:0038138; P:ERBB4-ERBB4 signaling pathway; ISO:RGD.
DR GO; GO:0072046; P:establishment of planar polarity involved in nephron morphogenesis; ISO:RGD.
DR GO; GO:0007507; P:heart development; ISS:UniProtKB.
DR GO; GO:0007595; P:lactation; ISS:UniProtKB.
DR GO; GO:0060749; P:mammary gland alveolus development; ISS:UniProtKB.
DR GO; GO:0030879; P:mammary gland development; IEP:RGD.
DR GO; GO:0060644; P:mammary gland epithelial cell differentiation; ISS: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; IMP:RGD.
DR GO; GO:0007399; P:nervous system development; ISS:UniProtKB.
DR GO; GO:0001755; P:neural crest cell migration; ISS:UniProtKB.
DR GO; GO:0042476; P:odontogenesis; IEP:RGD.
DR GO; GO:0021889; P:olfactory bulb interneuron differentiation; ISS:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
DR GO; GO:0060045; P:positive regulation of cardiac muscle cell proliferation; ISS:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; IMP:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IMP:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0046326; P:positive regulation of glucose import; IMP:RGD.
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; ISS:UniProtKB.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISO:RGD.
DR GO; GO:0071073; P:positive regulation of phospholipid biosynthetic process; IMP:RGD.
DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; ISO:RGD.
DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; ISS:UniProtKB.
DR GO; GO:0032230; P:positive regulation of synaptic transmission, GABAergic; IMP:RGD.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0030334; P:regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0042542; P:response to hydrogen peroxide; IEP:RGD.
DR GO; GO:0032570; P:response to progesterone; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR GO; GO:0007165; P:signal transduction; ISO:RGD.
DR GO; GO:0043129; P:surfactant homeostasis; IMP:RGD.
DR GO; GO:0007416; P:synapse assembly; ISO:RGD.
DR GO; GO:0060074; P:synapse maturation; IMP:RGD.
DR GO; GO:0021537; P:telencephalon development; IEP:RGD.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; ISS: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 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_0000016675"
FT CHAIN 676..1308
FT /note="ERBB4 intracellular domain"
FT /evidence="ECO:0000250"
FT /id="PRO_0000396799"
FT TOPO_DOM 26..651
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 652..675
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 MOTIF 676..684
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250"
FT MOTIF 1032..1035
FT /note="PPxy motif 1"
FT MOTIF 1298..1301
FT /note="PPxY motif 2"
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: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 253
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 358
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 1046..1062
FT /note="SEIGHSPPPAYTPMSGS -> N (in isoform JM-A CYT2)"
FT /evidence="ECO:0000303|PubMed:15355992"
FT /id="VSP_022150"
FT CONFLICT 406
FT /note="T -> S (in Ref. 2; AAQ77348/AAQ77349)"
FT /evidence="ECO:0000305"
FT CONFLICT 596
FT /note="V -> G (in Ref. 2; AAQ77348/AAQ77349)"
FT /evidence="ECO:0000305"
FT CONFLICT 951
FT /note="I -> M (in Ref. 2; AAQ77348/AAQ77349)"
FT /evidence="ECO:0000305"
FT CONFLICT 1062
FT /note="S -> N (in Ref. 2; AAQ77348 and 4; AAC53051)"
FT /evidence="ECO:0000305"
FT CONFLICT 1080..1082
FT /note="PYT -> SYR (in Ref. 4; AAC53051)"
FT /evidence="ECO:0000305"
FT CONFLICT 1082
FT /note="T -> R (in Ref. 2; AAQ77348/AAQ77349)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1308 AA; 146958 MW; D944BB0996A08B41 CRC64;
MKLATGLWVW GSLLVAARTV QPSASQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM
GNLEITSIEH NRDLSFLRSI REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF
LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNMTLVST
IGSSGCGRCH KSCTGRCWGP TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG
PKDTDCFACM NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD
SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS SNIDKFINCT
KINGNLIFLV TGIHGDPYNA IDAIDPEKLN VFRTVREITG FLNIQTWPPN MTDFSVFSNL
VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST
VNQRIVIRDN RRAENCTAEG MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD
GEFREFENGS ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDVLQGA
NSFIFKYADQ DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG
LFILVIMALT FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR
VKVLGSGAFG TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASVDHPHL
VRLLGVCLSP TIQLVTQLMP HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV
HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ
SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY IVMVKCWMID
ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE
EYLVPQAFNI PPPIYTSRTR IDSNRSEIGH SPPPAYTPMS GSQFVYQDGG FATQQGMPMP
YTATTSTIPE APVAQGATAE MFDDSCCNGT LRKPVVPHVQ EDSSTQRYSA DPTVFAPERN
PRAELDEEGY MTPMHDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHS ASSGPPKAED
EYVNEPLYLN TFTNALGNAE YMKNSLLSVP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ
EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTMLPPPP YRHRNTVV
