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FLASH GENE
Symbol ERBB4 contributors: mct - updated : 03-10-2013
HGNC name v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)
HGNC id 3432
Corresponding disease
ALS19 amyotrophic lateral sclerosis 19
Location 2q34      Physical location : 212.240.441 - 213.403.352
Synonym name
  • avian erythroblastic leukemia viral (v-erb-b2) oncogene homolog 4
  • receptor tyrosine-protein kinase erbB-4
  • tyrosine kinase-type cell surface receptor HER4
  • Synonym symbol(s) HER4, MGC138404, p180erbB4
    EC.number 2.7.10.1
    DNA
    TYPE functioning gene
    STRUCTURE 1162.91 kb     28 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    CRYGB 2q33-q35 crystallin, gamma B CRYGA 2q33-q35 crystallin, gamma A LOC389073 2 similar to RIKEN cDNA D630023F18 LOC130429 2q34 similar to 40S ribosomal protein SA (P40) (34/67 kDa laminin receptor) (Colon carcinoma laminin-binding protein) (NEM/1CHD4) (Multidrug resistance-associated protein MGr1-Ag) IDH1 2q32-qter isocitrate dehydrogenase 1 (NADP+), soluble PIP5K3 2q34 phosphatidylinositol-3-phosphate/phosphatidylinositol 5-kinase, type III LOC391478 2 similar to ARP2/3 complex 41 kDa subunit (P41-ARC) (Actin-related protein 2/3 complex subunit 1B) PTHR2 2q33 parathyroid hormone receptor 2 LOC130195 2q34 similar to Heat shock cognate 71 kDa protein LOC391479 2 similar to Chain  , Heat-Shock Cognate 70 Kd Protein (44 Kd Atpase N-Terminal Fragment) (E.C.3.6.1.3) Mutant With Thr 204 Replaced By Val (T204v) LOC389074 LOC391480 2 similar to PKP4 protein MAP2 2q34 microtubule-associated protein 2 FLJ33496 SNAI1L1 2q34 snail homolog 1 like 1 (Drosophila) RPE 2q32-q33.3 ribulose-5-phosphate-3-epimerase FLJ23861 2q34 hypothetical protein FLJ23861 ACADL 2q34 acyl-Coenzyme A dehydrogenase, long chain MYL1 2q34 myosin, light polypeptide 1, alkali; skeletal, fast LANCL1 2q33-q35 LanC lantibiotic synthetase component C-like 1 (bacterial) CPS1 2q35 carbamoyl-phosphate synthetase 1, mitochondrial PRO0132 2q34 PRO0132 protein ERBB4 2q34 v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian) LOC200595 2q35 similar to chromosome 20 open reading frame 81 ZNFN1A2 2qter zinc finger protein, subfamily 1A, 2 (Helios) PF20 2q35 PF20
    RNA
    TRANSCRIPTS type messenger
    text
  • alternatively spliced producing juxtamembrane (JM-a and JM-b) and cytoplasmic (CYT-1 and CYT-2) isoforms (PMID; 20943952)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    28 splicing 11941 146.8 1308 - 2010 20886074
  • efficiently endocytosed
  • precursor
  • having PPXY motif within the CYT-1-specific sequence that lacks from CYT-2, necessary both for ubiquitination and endocytosis of CYT-1 isoforms and provided a binding site for a WW domain-containing ubiquitin ligase ITCH
  • JM-a/CYT-1
  • fibroblasts expressing ERBB4 JM-a demonstrated enhanced ERBB4 autophosphorylation, growth, and survival
  • - splicing 40 - 15 heart, cerebellum 2010 20943952
  • cells overexpressing ERBB4 JM-b underwent starvation-induced death
  • - splicing - - - cerebellum 2001 11391800
    - splicing - - - developing fetal cerebellum only 2001 11391800
    27 splicing 11893 - 1292 - 2010 20886074
  • precursor
  • also called JM-a, CYT-2
  • novel splice isoforms of ErbB4, whereby exon 3 is skipped (del.3). ERBB4 del.3 transcripts exist as CYT-2 isoforms and are predicted to produce truncated proteins
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Endocrineneuroendocrine   moderately
     parathyroid   highly
    Lymphoid/Immunespleen   moderately
    Nervousbrainhindbraincerebellum moderately
    Reproductivefemale systembreastmammary gland highly
     male systemtestis  moderately
    Urinarykidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumcardiac   Homo sapiens
    Muscularstriatumskeletal highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Muscularmyocyte Homo sapiens
    cell lineage
    cell lines breast carcinoma cell line
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a single transmembrane protein with extensive homology to the epidermal growth factor receptor
  • extracellular juxtamembrane domain (JM-a and JM-b forms)
  • intracellular cytoplasmic domain (CYT-1 and CYT-2)
  • specific N-glycan in domain III playing an essential role in regulating receptor dimerization and transforming activity
  • a cytoplasmic catalytic domain with a sequence in the C terminal terminal binding the PDZ domain of MAGUKs protein
  • a putative NLS with three clusters of basic amino acids (RRRHIVRKRTLRR (amino acids 645-657)) in the juxtamembrane region
  • conjugated GlycoP
    mono polymer homomer , heteromer , dimer , trimer
    HOMOLOGY
    interspecies ortholog to murine Erbb4
    ortholog to rattus Erbb4
    intraspecies homolog to avian erythroblastic leukemia v(erb-b) viral oncogene 4
    Homologene
    FAMILY
  • epidermal growth factor family
  • type I receptor tyrosine kinase subfamily
  • CATEGORY enzyme , protooncogene , receptor membrane tyrosine kinase
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,mitochondria,matrix
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    text
  • integral to plasma membrane; type I membrane protein
  • localizes to the nucleus as a full-length protein (PMID;
  • basic FUNCTION
  • receptor tyrosine kinase activity
  • neuregulin beta 1 receptor, high affinity
  • regulates cell proliferation and differentiation
  • involved in the regulation of the timing of astrogenesis in developing brain
  • required for mammary gland development and lactation
  • causes reversal regulation of PPP2R4 in the Shc signal transduction pathway in cancer cells
  • NRG1/ERBB4 signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex
  • controls the development of inhibitory circuitries in the cerebral cortex by cell-autonomously regulating the connectivity of specific GABA-containing interneurons
  • in the fetal lung, ERBB4 functions as a transcriptional regulator for surfactant protein B (SFPTB), the most critical surfactant protein gene
  • directly regulates important aspects of fetal lung maturation that help prepare for the fetal-neonatal transition
  • ERBB4 signaling modulates potentially proliferation and polarization, cellular functions critical for the development of epithelial ducts in the kidney
  • plays a role in the DNA damage response induced by doxorubicin in cardiac myocytes
  • receptor tyrosine kinase implicated in the development and homeostasis of the heart, central nervous system, and mammary gland
  • new role for NRG1/ERBB4 signaling in regulating oligodendrocyte precursors migration selectively during early stages of CNS development
  • in the fetal lung, functions as a transcriptional co-factor and regulates the timely onset of fetal SFTP expression
  • is a critical upstream regulator of TTF1 in type II epithelial cells and that this interaction is important for SFTPB regulation
  • CELLULAR PROCESS cell life, differentiation
    cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS development , nervous system
    PATHWAY
    metabolism
    signaling
    a component
  • part of a ternary complex made of one DLG4 and two ERBB4
  • homodimer or heterodimer with each of the other ERBB receptors
  • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
  • protein
  • related membrane-associated guanylate kinases
  • SNT2B1
  • SNT2B2
  • interacting with NRG1, NRG2, NRG3
  • NRG/ERBB signaling maintains high efficacy of synaptic transmission by stabilizing the postsynaptic apparatus via phosphorylation of DTNA
  • directly activates STAT5A (phosphorylation of STAT5A are obligatory events regulating ERBB4-mediated activation of STAT5A)
  • BTC acts via both the EGF receptor, located on Neural stem cells (NSCs), and ERBB4, located on neuroblasts, with the latter explaining why its effects are distinct from those of EGF itself
  • direct regulator of hypoxia-inducible factor-1A (HIF1A) signaling
  • PIAS3 is a novel interaction partner of ERBB4 soluble intracellular domain (ICD)
  • CADM1 interacts with ERBB4 and regulates the development of excitatory synapses via the regulation of ERBB4 activity in GABAergic neurons
  • ERBB4 is an upstream regulator of TTF1 and regulates SFTPB expression via this pathway in alveolar type II cells
  • BTC binds and activates EGFR and ERBB4 homodimers
  • PTPN21 exerts pro-neuronal survival and neuritic elongation via ERBB4/NRG3 signaling
  • cell & other
    REGULATION
    activated by NRG1, NRG3, NRG2
    inhibited by WWP1 in breast cancer
    Other cleaved by metalloprotease after ligand binding
    regulated by N-glycosylation that controls ErbB signaling by various mechanisms
    ASSOCIATED DISORDERS
    corresponding disease(s) ALS19
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral germinal mutation      
    juxtamembrane splice variants in same chidhood medulloblastoma
    tumoral     --over  
    in lung carcinoma
    tumoral somatic mutation      
    in melanoma
    Susceptibility
  • to schizophrenia
  • to left ventricular outflow tract (LVOT) defects
  • Variant & Polymorphism other
  • interaction between variants in NRG1 and ERBB4 might contribute to susceptibility for schizophrenia
  • a specific haplotype in intron 3 of ERBB4 positively associated with the combined LVOT defects phenotype
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerskin 
    targeting of ERBB4 with small-molecule inhibitors should be considered as a therapeutic approach for the many individuals with melanoma
    ANIMAL & CELL MODELS
    astrogenesis occurs precociously in ErbB4 knock-out mice