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FLASH GENE
Symbol ERBB3 contributors: mct/np/shn/pgu - updated : 20-06-2018
HGNC name v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian)
HGNC id 3431
Corresponding disease
LCCS2 lethal congenital contracture syndrome 2
Location 12q13.2      Physical location : 56.473.891 - 56.497.127
Synonym name
  • tyrosine kinase-type cell surface receptor
  • lethal congenital contracture syndrome 2
  • receptor tyrosine-protein kinase erbB-3 precursor
  • Synonym symbol(s) HER3, ERB3, ErbB-3, c-erbB3, erbB3-S, MDA-BF-1, p180-ErbB3, p45-sErbB3, p85-sErbB3, MGC88033, LCCS2
    EC.number 2.7.10.1
    DNA
    TYPE functioning gene
    STRUCTURE 23.24 kb     28 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked   status confirmed
    Map cen - D12S1707 - D12S1632 - ERBB3 - D12S1644 - D12S1691 - qter
    Physical map
    RDH5 12q13-q14 retinol dehydrogenase 5 (11-cis and 9-cis) CD63 12q12-q13 CD63 antigen (melanoma 1 antigen) GDF11 12q12 growth differentiation factor 11 CIP29 12q13.13 cytokine induced protein 29 kDa ORMDL2 12q12 ORM1-like 2 (S. cerevisiae) DNAJ 12q13.13 DnaJ protein MMP19 12q14 matrix metalloproteinase 19 PYM 12q13.13 PYM protein DGKA 12q13.3 diacylglycerol kinase, alpha 80kDa SILV 12q13-q14 silver homolog (mouse) CDK2 12q13.3 cyclin-dependent kinase 2 SUOX RAB5B 12q13 RAB5B, member RAS oncogene family ZNFN1A4 12q13 zinc finger protein, subfamily 1A, 4 (Eos) RPS26 12q14 ribosomal protein S26 ERBB3 12q13.3 v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) PA2G4 12q13 proliferation-associated 2G4, 38kDa RPL41 12q14 ribosomal protein L41 FLJ14451 12q13.13 hypothetical protein FLJ14451 MBC2 12q13.13 hypothetical protein FLJ14451 MLC1SA 12q13.13 hypothetical protein FLJ14451 MYL6 12q12 myosin, light polypeptide 6, alkali, smooth muscle and non-muscle SMARCC2 12q13-q14 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily c, member 2 RNF41 12q13.13 ring finger protein 41 MGC2731 12q13.13 hypothetical protein MGC2731 SLC39A5 12q13.3 solute carrier family 39 (metal ion transporter), member 5 FLJ34236 12q13.13 hypothetical protein FLJ34236 FLJ32452 12q13.13 hypothetical protein FLJ32452 CS 12p11-qter citrate synthase TMEM4 12q15 transmembrane protein 4 USP52 12q13.2-q13.3 ubiquitin specific protease 52
    RNA
    TRANSCRIPTS type messenger
    text
  • additional splice variants have also been reported, but they have not been thoroughly characterized
  • alternative transcription initiation results in the formation of a nuclear variant of ErbB3 (nuc-ErbB3) primary Schwann cells (PMID:21451047)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    28 splicing 5511 160 1342 cell membrane (single-pass type I membrane protein) 1990 2164210
  • a 19 aa peptide signal of 2 kda
  • a 1323 aa mature peptide of 146.1 kda
  • 3 splicing 1050 - 183 secreted protein 1993 7685162
  • modulating the activity of the membrane-bound form
  • a 19 aa signal peptide of 2 kda
  • a 164 aa mature peptide of 18.1 kda
  • EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Digestivemouth   highly
    Hearing/Equilibriumearinnercochlea highly
    Nervousbrain    
    Respiratoryrespiratory tracttrachea  predominantly
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    cell lineage
    cell lines mammary tumor MDA-MB415 and MDA-MB453 cell lines (
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a 19 aa signal peptide (2 kda)
  • an extracellular cysteine-rich ligand binding domain (heparin-binding site)
  • a single transmembrane (1TM) protein with extensive homology to the epidermal growth factor receptor, lacking the C terminal catalytic domain (kinase domain binds ATP, but is catalytically inactive and can serve as an activator of the EGFR kinase domain)
  • a furin-like cystein rich region
  • a tyrosine kinase catalytic domain
  • specific N-glycan in domain III playing an essential role in regulating receptor dimerization and transforming activity
  • a putative NLS with three clusters of basic amino acids (RRRHIVRKRTLRR (amino acids 645-657)) in the juxtamembrane region
  • a functional nuclear localization signal sequence (
  • mono polymer homomer , heteromer , dimer
    isoforms Precursor a 1323 aa mature peptide of 146.1 kda
    HOMOLOGY
    interspecies ortholog to ERBB3, Pan troglodytes
    ortholog to Erbb3, Rattus norvegicus
    ortholog to Erbb3, Mus musculus
    intraspecies homolog to viral (v-erb-b) oncogene 3
    homolog to IGF1R
    Homologene
    FAMILY
  • epidermal growth factor receptor (EGFR) subfamily
  • CATEGORY enzyme , protooncogene , receptor membrane tyrosine kinase
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,nucleus
    text
  • apical and lateral plasma membrane
  • basic FUNCTION
  • acting as a receptor tyrosine kinase
  • acting as a neuregulin beta 1 receptor low affinity
  • acting as an heregulin receptor
  • acting as an epidermal growth factor receptor
  • activator of the phosphatidylinositol-3-kinase/Akt pathway, regulating cell survival and vesicle trafficking, essential for the generation of precursors of Schwann cells that normally accompany peripheral axons of motor
  • neurons
  • regulating PI3K/Akt pathway, a critical survival pathway in neurons and in most cell types, through heregulin
  • contributes to tumorigenic conversion and that their expression levels may be increased by signaling initiated by TGF-alpha (
  • ERBB3 signaling may contribute to metastatic progression of melanoma
  • ERBB3 function is an important aspect of ERBB2-mediated breast cancer, prompting the need for a more thorough understanding of ERBB3 expression and dysregulation in breast cancer
  • both ERBB3 and RNF41 are dysregulated post-transcriptionally in tumors
  • functions in part, by modulating the activity of ERBB3
  • plays an essential role in ERBB2-mediated transformation, tumor progression, and drug resistance
  • regulates the balance of differentiated breast epithelial cell types by regulating their growth and survival through autocrine- and paracrine-signaling mechanisms
  • is catalytically impaired but binds ligand, and its kinase domain allosterically activates its partners
  • high levels of ERBB2, ERBB3 may not only be a target of constitutive phosphorylation and driver for enhanced cancer cell survival
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development
    text
  • heart development
  • peripheral nervous system development
  • PATHWAY
    metabolism
    signaling signal transduction
  • transmembrane receptor protein tyrosine kinase signaling pathway
  • PI3K/Akt pathway
  • a component
  • dimerizing with the ligand less receptor ERBB2
  • heterodimerizing with ERBB2 for catalytic function
  • heterodimerizing with each of the other ERBB receptors
  • heterodimers of the ligand-binding–deficient ERBB2 (HER2) receptor and the kinase impaired ERBB3 (HER3) create a potent mitogenic signal
  • INTERACTION
    DNA
  • chromatin (
  • RNA
    small molecule nucleotide,
  • ATP
  • protein
  • neu differentiation factor, NDF (
  • Neuregulin-2, NRG2 (
  • p23/p198 (
  • proliferation-associated 2G4, 38kDa, PA2G4 (
  • angiotensin II receptor sub-type AT2 (
  • focal adhesion kinase, FAK (
  • Sos Ras exchange protein (
  • gp130 (
  • Epidermal growth factor, EGF (
  • E3 ubiquitin-protein ligase NRDP1, NRDP1 (
  • NTAK
  • CSPG5
  • associates with RNF41 which stimulates its ubiquitination and degradation by proteasomes
  • regulator of G-protein signaling 4, RGS4 (
  • Tetraspanin CD82 (
  • v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian), ERBB2 (
  • sclerostin and the C-terminal portion of the receptor tyrosine-protein kinase ERBB3
  • Neuregulin-1, NRG1 (
  • NRG1 is the ligand for ERBB3 and 4, members of the epidermal growth factor family of receptors that are involved in the genesis and progression of a number of cancers
  • interaction of CADM1 with ERBB3 inhibits the NRG1-induced ERBB3/ERBB2 signaling in epithelial cells
  • APIP plays an essential role in ERBB3 signaling as a positive regulator for tumorigenesis
  • cell & other
    REGULATION
    activated by NRG1, NRG2
    NTAK
    Other regulated expression by Sox10 during development of the neural crest
    phosphorylated ERBB3 is a particularly potent signaling molecule because it activates the PI3K/AKT pathway
    regulated by N-glycosylation that controls ErbB signaling by various mechanisms
    translation of nuclear variant of ErbB3 is regulated by Neuregulin-1 (
    ASSOCIATED DISORDERS
    corresponding disease(s) LCCS2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in a subset of mammary tumors
    tumoral   amplification --over  
    amplification and/or overexpression reported in numerous cancers, including prostate, bladder, and breast tumors
    tumoral     --over  
    in pilocytic astrocytoma
    tumoral     --over  
    strongly associated with tumor progression and poor prognosis of patients with gastric cancer
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductivebreast
    therapeutic inhibitors of ERBB3 should be used in combination with HER2 inhibitors and PI3K pathway inhibitors in patients with ERBB2- and PI3K-dependent cancers
    cancerlung 
    small inhibitory RNA (siRNA) showing promise as a therapeutic approach to treatment of lung adenocarcinoma
    cancerskin 
    targeting ERBB3 activation and downstream genes may provide novel therapeutic interventions for malignant melanoma
    cancerdigestivestomach
    new prognostic factor and a target of treatment in gastric cancer
    cancerreproductivebreast
    ERBB3 ablation may be therapeutically effective in tumors where ErbB3 engages PI3K/Akt signaling
    ANIMAL & CELL MODELS