Selected-GenAtlas references SOURCE GeneCards NCBI Gene Swiss-Prot Ensembl
HGNC UniGene Nucleotide OMIM UCSC
Home Page
FLASH GENE
Symbol ERBB2 contributors: mct - updated : 05-03-2020
HGNC name v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)
HGNC id 3430
Location 17q12      Physical location : 37.844.392 - 37.884.914
Synonym name
  • herstatin
  • epidermal growth factor (EGF) receptor
  • c-erb B2/neu protein
  • tyrosine kinase-type cell surface receptor HER2
  • metastatic lymph node gene 19 protein
  • proto-oncogene c-ErbB-2
  • CD340 antigen
  • proto-oncogene Neu
  • human epidermal growth factor receptor 2
    • Synonym symbol(s) HER2, NGL, NEU, TKR1, HER-2, c-erb B2, ERBB-2, CD340, MLN 19
    EC.number 2.7.10.1
    DNA
    TYPE functioning gene
    STRUCTURE 40.58 kb     30 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   enhancer   transcription factor
    text structure
  • TFAP2C, a known regulator of ERBB2, binds to HGE (ERBB2 gene body enhancer) and is required for its enhancer function and DNA methylation in the HGE region inhibits the histone modifications characterizing enhancer and is inversely correlated with ERBB2 expression in breast cancer samples
  • differential methylation in specific CpG sites modify the binding of Sp1 to the promoter of ERBB2, and DNA methylation in the ERBB2 locus may contribute to the variable expression of ERBB2 in human myocardium
    • MAPPING cloned Y linked N status confirmed
    Map see NF1 NF1
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    27 - 4624 137.91 1255 - 2018 30543586
  • a 27 exons variant
  • lacking exons 1, 2, 3 and 4
  • encoding for the longest product
    • 30 splicing 4816 134.72 1225 secreted fetal liver, kidney 2018 30543586
  • a 30 exon variant
  • lacking exon 5
  • retaining intron 8 subdomain I, II
    • 31 - 4940 - 1240 - 2018 30543586
    18 - 2590 - 603 - 2018 30543586
    26 - 4411 - 1055 - 2018 30543586
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   highly
    Cardiovascularheartventricle    Homo sapiens
    Endocrinepancreas   highly
    Reproductivemale systemprostate  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    Muscularstriatumcardiacmyocardium  Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, fetal
    Text kidney, liver and in the developing nervous system
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • an extracellular domain with four subdomains I-IV
  • a single transmembrane (TM) protein with extensive homology to the epidermal growth factor receptor
  • a cytoplasmic catalytic domain
  • a Blocking ErbB2 Degradation or BED domain, that is the factor restricting the ligand-induced degradation of ERBB2
  • 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
    • conjugated GlycoP , PhosphoP
    mono polymer homomer , heteromer , dimer
    HOMOLOGY
    interspecies homolog to rattus Erbb2 (88.13 pc)
    homolog to murine Erbb2 (87.73 pc)
    homolog to zebrafish erbb2 (59.08 pc)
    intraspecies homolog to avian erythroblastic leukemia viral (v-erb-b) oncogene 2
    Homologene
    FAMILY
  • epidermal growth factor (EGF) receptor family
  • class I tyrosine protein kinase family
  • erythroblastosis oncogene B (ERBB)-like oncogene family
    • CATEGORY enzyme , protooncogene , signaling , receptor membrane
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleolus
    text
  • type I membrane protein
  • detected in the nucleus
    • basic FUNCTION
  • acting as a coreceptor for multiple stroma-derived growth factors i.e EGF-like ligands and neuregulins, and as a coreceptor for GPCR signaling in the heart
  • involved in androgen receptor transactivation of inducing prostate-specific antigen (PSA) through the MAP kinase pathway
  • playing a critical role for normal cardiac function and prevention of dilated cardiomyopathy (together with ERBB4 and neuregulin)
  • modulating epidemal growth factor signaling pathways resulting in growth arrest
  • required for the distal morphogenesis of the mammary gland
  • playing a pivotal role for integrating signaling networks involving multiple classes of extracellular signals
  • requires ITGA5 for anoikis resistance via SRC regulation of receptor activity in human mammary epithelial cells
  • ERBB2 regulation having important implications in cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor
  • controls microtubule capture by recruiting MACF1 to the plasma membrane of migrating cells
  • may be dependent on ERBB3 to drive growth and survival of breast cancer cells
  • novel function of nuclear ERBB2 in enhancing rRNA gene transcription by RNA polymerase-I (RNA Pol I)
  • nuclear ERBB2 functions as a regulator of rRNA synthesis and cellular translation, which may contribute to tumor development and progression
  • positive activation loop between ADAM12 and ERBB2 that may contribute to head and neck squamous cell carcinoma (HNSCC) progression
  • is an orphan receptor that tyrosine phosphorylates its heterodimerization partners
  • high levels of ERBB2, ERBB3 may not only be a target of constitutive phosphorylation and driver for enhanced cancer cell survival
  • ERBIN is required for remyelination of regenerated axons after injury, probably by regulating ERBB2 and NRG1 levels
  • ERBB2 activation inhibits the pro-apoptotic function of MAP3K11, which plays a mechanistic role in mediating anti-tumor activities of ERBB2-directed therapies
  • signaling of growth factor receptor ERBB2 is critical for myocyte proliferation and trabeculation
  • unlike other ERBB family members, ERBB2 is resistant to internalization and degradation, and remains at the cell surface to signal for prolonged periods after it is activated
  • plays a pivotal role during heart development and is essential for normal cardiac function, particularly during episodes of cardiac stress
  • both ERBB2 and ERBB3 are essential for normal proliferation of skin keratinocytes, but in contrast to ERBB3, ERBB2 is essential for migration of human keratinocytes
  • ERBB2 and AKT1 are important for cranial neural crest (CNC) migration, but other ERBB receptors and AKT1-independent signaling pathways are implicated
    • CELLULAR PROCESS cell cycle, division
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism
    signaling signal transduction
    growth factors pathway
    a component
  • heterodimerizing with other ERBBs, secreted by ligand-binding members of EGFR family
  • heterodimer with ERBB3, ERBB4
  • complexes with cofilin, ERBB2 and PLCG1
  • heterodimers of the ligand-binding–deficient ERBB2 (HER2) receptor and the kinase impaired ERBB3 (HER3) create a potent mitogenic signal
    • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
    • protein
  • AP2 for regulation by oestrogen
  • WITH GRB7 (to regulating cell proliferation)
  • PRKCABP
  • PLXNB1
  • interaction with LNX1, an E3 ubiquitin ligase that can target interacting proteins for degradation through ubiquitination
  • DOCK7 functions as an intracellular substrate for ERBB2 to promote Schwann cell migration to promote Schwann cell migration
  • nuclear ERBB2 physically associates with beta-actin and RNA Pol I, coinciding with active RNA Pol I transcription sites in nucleoli
  • NRG/ERBB signaling maintains high efficacy of synaptic transmission by stabilizing the postsynaptic apparatus via phosphorylation of DTNA
  • NRG1 inhibited the GDNF-induced neuronal differentiation and GDNF negatively regulated NRG1-signaling by down-regulating the expression of its receptor, ERBB2
  • imbalanced NRG1 isoforms and downregulated ERBIN may contribute to the dysregulation of ERBB2 signaling in the development of diabetic peripheral neuropathy (DPN)
  • LINGO1 can directly bind to ERBB2, block ERBB2 translocation into lipid rafts, and inhibit its phosphorylation for activation
  • ERBIN is an ERBB2 regulator for breast tumor formation and progression
  • KRT19 phosphorylated by AKT1 could bind ERBB2 on the plasma membrane and stabilized ERBB2 via inhibition of proteasome-mediated degradation of ERBB2
  • ERBB2, MYC, WIF1, RBM38, PTEN, are involved in the HOTAIR regulation network
  • positive feedback regulation between FASN and ERBB2 expression and phosphorylation in osteosarcoma (OS) cells
  • SRSF3 and HNRNPH1 are the first splicing factors identified which regulate the production of these functionally distinct ERBB2 splice variants and therefore maybe important for the regulation of ERBB2 signaling
  • interactions between ATP2B2 and ERBB2 in specific actin-rich membrane domains
  • FASN, ERBB2-mediated glycolysis is required for breast cancer cell migration
  • ERBB2 downregulates PERP by activating an ERBB2 effector protein kinase MEK that blocks detachment-induced EGFR loss in a manner that requires the presence of a signaling protein SPRY2
  • EPX is a novel ligand for the ERBB2
  • NUMB and NUMBL interacted with small GTPase RAB7A to transition ERBB2 from early to late endosome for degradation
  • SLC9A3R1 acts with ATP2B2 to regulate ERBB2 signaling and membrane retention in breast cancers
  • interact with the chaperone, HSP90AB1, and the calcium pump, ATP2B2, within specific plasma membrane domains that protrude from the cell surface
  • significant role of ERBB2 methylation by protein lysine methyltransferase SMYD3 in ERBB2 homodimerization
  • both IGF1 and leptin can modulate EGFR and ERBB2 signaling pathways in obesity-related carcinogenesis
  • SEMA3C drives activation of multiple RTKs including EGFR, ERBB2, and MET in a cognate ligand-independent manner via PLXNB1
  • ERBB2 interacts with BECN1 in breast cancer cells and inhibits autophagy
  • DDX6 protein acted as an RNA-binding protein for ERBB2 and FGFR2 mRNAs and positively regulated their post-transcriptional processes
  • SMYD2 affects cell proliferation, invasion, and apoptosis of colon cancer cells via the regulation of ERBB2/FUT4 signaling pathway
  • directly interacts with NEDD8 and NAE1, whereas ERBB2 protein expression is decreased by neddylation depletion
    • cell & other
    REGULATION
    activated by NRGs isoforms
    induced by PIN1 (PIN1 amplifies EGF signaling in breast cancer cells through its interaction with MAP2K1 and then enhances ERBB2 expression)
    inhibited by its alternative isoform herstatin that disrupts ERBB2 dimers
    ETV4
    Other regulated by N-glycosylation that controls ErbB signaling by various mechanisms
    neddylation of ERRB2 is a new post-translational modification that controls its expression and oncogenic activity in human breast cancer
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in primary gastric cancer and prostate carcinoma with metastasis and poor prognosis, pancreas, colon and ovary carcinoma, cholangiocarcinoma
    tumoral       gain of function
    in primary breast and uterus endometrial cancer and in low grade osteosarcoma with increased survival
    tumoral somatic mutation      
    in dilated cardiomyopathy
    tumoral     --over  
    in neuro/glioblastoma and in non-small cell lung cancer
    tumoral   amplification    
    in many types of cancer, including breast cancer
    tumoral somatic mutation      
    in the lung squamous cell carcinoma (kinase domain mutation )
    tumoral     --over  
    in breast cancer cells with poor prognostic (with enhanced tumorigenicity, propensity to metastasize and resistance to endocrine therapy)
    tumoral   amplification    
    loss of beclin 1 and ERBB2 amplification (both on 17q21) in breast cancers
    tumoral     --over  
    patients breast cancer with higher CCNA2 and ERBB2 expressions had significantly shorter disease-free survival periods
    tumoral   amplification    
    may be involved in tumor progression in early gastric cancer
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker overexpression in breast cancer cells are known to be poor prognostic markers and are strong predictors of benefit from treatment with ERBB2-targeting agents
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductivebreast
    selected RNA aptamer is a potential cancer imaging agent by targeting malignant cells of breast cancer overexpressing the ERBB2 receptor
    cancerreproductivebreast
    blockade of ERBB2:TGFB crosstalk may significantly enhance the efficiency of conventional therapies in breast cancer patients with ERBB2 overexpression
    cancerreproductivebreast
    anti-ERBB2 human compact antibody-RNase (Erb-hcAb-RNase) could be a promising candidate for the immunotherapy of ERBB2-positive tumours
    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
    cancerreproductivebreast
    interactions between ATP2B2 and ERBB2 may represent therapeutic targets for breast cancer
    cancerreproductivebreast
    strategies to block ERBB2/BECN1 binding and/or increase autophagy may represent a new therapeutic approach for ERBB2-positive breast cancers (PMID: 29610308)
    cancerreproductivebreast
    interactions between ATP2B2 and ERBB2 may represent therapeutic targets for breast cancer
    miscelleaneousurinarychronic kidney disease
    most promising targets for future therapeutic development in Polycystic kidney disease (PKD)are those that target upstream signaling events at cell membranes, such as the vasopressin-2 receptor (AVPR2), EGFR/ERBB2
    ANIMAL & CELL MODELS