ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian))

2012-05-01   Smita Awasthi , Anne W Hamburger 

University of Maryland School of Medicine, Department of Pathology, University of Maryland Greenebaum Cancer Center, USA




Atlas Image
The alignment of ERBB3 mRNA to its genomic sequence.


The ERBB3 gene, which maps to human chromosome 12q13.2, is 23.2 kb in size and consists of 28 exons. The gene for the extracellular ligand binding domain of ErbB3 has 43-45% homology with EGFR and ERBB2 and 56-67% homology with ERBB4. The cytoplasmic tyrosine kinase domain sequences have 60-63% homology with those of the other ErbB receptors (Kraus et al., 1989).


The ERBB3 promoter region is GC rich (65%) and, like EGFR, does not contain a TATA box. A proximal promoter was observed within 600 bp flanking Exon1. AP2-1 (OB2-1) and Fox3a have been demonstrated to be functional transcriptional regulators at upstream start sites (Skinner and Hurst, 1993). A Sox10 regulated enhancer has been identified at chr12:54763065-54763421 in neural crest derived cells. The human ERBB3 gene is transcribed as a 6.2 kb message of 4080 nucleotides and 1342 codons specifying the full-length protein. There are four additional alternate transcripts of 1.6, 1.7, 2.1 and 2.3 kb generated by intron read through. At least three of these transcripts code for truncated, secreted soluble forms of ERBB3 (Lee and Maihle, 1998).


None reported.


Atlas Image
Linear schematic of ErbB3. Functional domains, including Signal Peptide (SP), the Ligand Binding Domain (LBD) with four subdomains (indicated by the red lines) transmembrane domain (TM), tyrosine kinase domain (TKD), and C-terminal signaling domain (SD).


The ERBB3 gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. The 6.2 kb transcript encodes a 148 kDa protein which is post-translationally glycosylated to yield a protein of 180 kDa (Kraus et al., 1989). The extracellular ligand-binding domain consists of four subdomains that change conformation in response to ligand. Domains I and III bind NRG with high affinity (Cho and Leahy, 2002). Due to substitutions in the kinase domain at aa 740, 759 and 834, ErbB3 lacks potent tyrosine kinase activity. However, recent data indicate that ErbB3 maintains some autophosphorylation activity (Shi et al., 2010). Heterodimerization with other ErbB family members, most notably ErbB2, is needed to convey biological signals through phosphorylation of downstream substrates, most notably AKT (Olayioye et al., 2000). In general, activation of these pathways leads to cell proliferation or differentiation. Alternate transcriptional splice variants encoding different isoforms have been characterized. Each alternate transcript encodes a truncated form of the ligand-binding domain of ErbB3 and can compete for binding with ligand, resulting in growth inhibition (Lee et al., 2001).
ErbB3 is post translationally regulated by a variety of mechanisms. After ligand binding, it is phosphorylated on 14 tyrosine residues by other ErbB family members (Kim et al., 1998) and under some circumstance c-Src, Met and BRK. Protein levels are regulated by the E3 ligase Nrdp1 and the Nrdp1 regulator USP8. USP8 itself is regulated by AKT, suggesting a feedback mechanism for ErbB activity (Wu et al., 2004).


ErbB3 is widely expressed in embryonic and adult tissues. It is expressed in epithelial cells of the gastrointestinal, respiratory, reproductive and urinary tracts as well as the skin and endocrine systems. It is highly expressed in neuronal tissue. Expression is relatively low in cells of the hematopoietic and immune systems (Kraus et al., 1989; Prigent et al., 1992).


ErbB3 is generally located in the plasma membrane. However, more recent studies indicate that ErbB3 is also localized to the nucleus (Offterdinger et al., 2002).


Activation and interactions
ErbB3 when localized at the plasma membrane binds different forms of neuregulin. The NRG family consists of a large group of isoforms, encoded by four genes with an EGF like C terminal portion and a variable N terminal region. Ligand binding leads to heterodimerization preferentially with ErbB2, but also other ErbB family members in secondary reactions (Pinkas-Kramarski et al., 1996). The transmembrane domain, which binds EBP1, is important for dimer stabilization (Jura et al., 2009). The cytoplasmic domain lacks potent tyrosine kinase activity. However, this domain has been shown to be an allosteric activator of the ErbB2 kinase domain (Zhang et al., 2006). The cytoplasmic tail of ErbB3 is phosphorylated by ErbB2 and is a signaling substrate. The 14 phosphorylated tyrosines in the C terminal signaling tail of ErbB3 can potentially dock numerous SH2/3 or PTB binding proteins involved in different biological pathways (Hynes and Lane, 2005).

Signaling and cellular activity
In contrast to other ErbB proteins, ErbB3 is not transforming when overexpressed or constitutively activated (Alimandi et al., 1995). Once phosphorylated by other ErbB family members or Src, Met or BRK, ErbB-3 can then bind numerous other signaling proteins. Activation of the PI-3 kinase-AKT pathway is especially important as there are six docking sites for the p85 subunit of PI-3K in the ErbB3 cytoplasmic tail at Tyr 1035, 1178, 1203/1205, 1257 and 1270. AKT regulates many downstream signaling nodes, in particular the two mTOR containing complexes. ErbB3 can also activate the MAPK pathway via its interactions with Grb7 (Tyr 1180,1243) and SHC (1309) (Hynes and Lane, 2005). Thus, ErbB3 is important in biological processes such as translation, apoptosis, nutrient sensing, metabolic regulation, angiogenesis and cell cycle control. Increased expression or activity of ErbB3 has been associated with resistance to EGFR and ErbB2 inhibitors (Sergina et al., 2007) and hormonal therapies (Liu et al., 2007). ErbB3 when localized in the nucleus acts as a transcription factor to regulate Cyclin D1 and β-casein genes (Andrique et al., 2012).

ErbB3 knock-out mice die by E13.5 with defective heart valve formation, but normal heart trabeculation. The animals show a generalized neural crest defects and lack Schwann cell precursors (Erickson et al., 1997). Due to the importance of ErbB3 in breast cancer, the role of ErbB3 in mammary development has been well-studied. ErbB3 is required for ductal morphogenesis in the mouse mammary gland (Stern, 2003). ErbB3 has also been implicated in maintenance of the luminal epithelial subtype in the breast (Balko et al., 2012).


The ErbB family has evolved from a single ligand-receptor combination in C. elegans (let-23 28% aa similarity) through Drosophila with one receptor (EGFR, 39% similarity) and four ligands to vertebrates, where four ErbB receptor bind multiple EGF-related ligands. The ERBB3 gene is conserved in chimpanzee (99% similarity), dog, cow, mouse (90%), rat, chicken, and zebrafish.



An A to G mutation is noted in intron 10 in Lethal Congential Contracture Syndrome 2 (LCCS2). LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord (Narkis et al., 2004).


Mutations in ErbB3 have been rarely noted in cancer. One of the 2 mutations reported was a missense mutation in exon 21 (2537 G > T) (Ser846Ile) detected in a rectal mucinous adenocarcinoma (1% of the total colon cancer samples. The other mutation was a silent mutation in exon 21 (2484 T > C) (His828His) detected in an invasive ductal carcinoma of the breast (2% of the total 60 breast cancers) (Jeong et al., 2006).

Implicated in

Entity name
Breast cancer
Increased expression of ErbB3 in breast cancer cells relative to normal epithelium is common. The increased expression is not due to genomic amplification (Gasparini et al., 1994). High ErbB3 expression has been correlated with both increased and poorer survival (Hamburger, 2008). The ErbB2/3 heterodimer is essential for proliferation of malignant mammary epithelial cells (Holbro et al., 2003). ErbB3 contributes to tamoxifen resistance (Liu et al., 2007) and activation of ErbB3 is also associated with resistance to ErbB directed tyrosine kinase inhibitors (Sergina et al., 2007).
Entity name
Ovarian cancer
Genomic amplification of ErbB3 has been noted in ovarian cancer and ErbB3 overexpression is associated with poor survival (Wilken et al., 2012). Truncated ErbB3 transcripts that code for soluble truncated proteins have been observed in ovarian cancer cell lines. Such soluble forms can inhibit proliferation (Maihle 2001). These soluble forms may have potential as markers of disease progression.
Entity name
Prostate cancer
Increased expression of ErbB3 has been noted in prostate cancer (Cheng et al., 2007; Koumakpayi et al., 2006). Activation of the ErbB2/3 heterodimer stabilizes Androgen Receptor contributing to hormone independent growth (Mellinghoff et al., 2004). NRG can activate the EBP1 Protein leading to decreased AR activity (Zhang and Hamburger, 2005). Nuclear localization of ErbB3 has been associated with both poorer and better prognoses. A secreted ErbB3 isoform has been shown to enhance bone metastasis (Chen et al., 2007).
Entity name
Pancreatic cancer
ErbB3 mRNA and protein has consistently been observed to be increased and associated with poor outcome (Friess et al., 1995).
Entity name
Lung cancer
Overexpression of ErbB3 generally correlates with poor prognosis (Yi et al., 1997). Several studies have indicated that ErbB3 affects clinical responsiveness to tyrosine kinase inhibitors. Cell lines with wild type and high levels of ErbB3 respond better to EGFR inhibitors (Engelman et al., 2005). In addition, gefitinib resistant NCSLC cells can amplify MET which then phosphorylates and activates ErbB3 and AKT pathways (Engelman et al., 2007). ErbB3 has also been implicated in inhibition of apoptosis in lung cancer cell lines (Sithanandam et al., 2005).
Entity name
The NRG1 gene was identified as a potential susceptibility gene for schizophrenia and defects in the expression of ErbB3 were also shown to occur in the prefrontal cortex of schizophrenic patients. However, currently the association between ErbB3 expression and schizophrenia is unclear (Corfas et al., 2004).
Entity name
Genome-wide association studies have identified associations between type I diabetes and single-nucleotide polymorphisms (SNP) at chromosome 12q13 surrounding the ERBB3 gene. The most significant association was observed with a SNP in exon 27 of the ERBB3 gene and an intergenic SNP (Keene et al., 2012). In addition, ErbB3 has been demonstrated to modulate antigen presenting cell function and type I diabetes risk (Jing et al., 2011).


Pubmed IDLast YearTitleAuthors
75386561995Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas.Alimandi M et al
222612532012ErbB3(80 kDa), a nuclear variant of the ErbB3 receptor, binds to the Cyclin D1 promoter to activate cell proliferation but is negatively controlled by p14ARF.Andrique L et al
221787562012The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium.Balko JM et al
176388622007A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells.Chen N et al
176344232007Bone microenvironment and androgen status modulate subcellular localization of ErbB3 in prostate cancer cells.Cheng CJ et al
121541982002Structure of the extracellular region of HER3 reveals an interdomain tether.Cho HS et al
151621662004Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia.Corfas G et al
174632502007MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.Engelman JA et al
93624611997ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice.Erickson SL et al
98158391997Mitoxantrone combined with paclitaxel as salvage therapy for platinum-refractory ovarian cancer: laboratory study and clinical pilot trial.Kurbacher CM et al
79082131994c-erbB-3 and c-erbB-2 protein expression in node-negative breast carcinoma--an immunocytochemical study.Gasparini G et al
184254252008The role of ErbB3 and its binding partners in breast cancer progression and resistance to hormone and tyrosine kinase directed therapies.Hamburger AW et al
128535642003The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation.Holbro T et al
158642762005ERBB receptors and cancer: the complexity of targeted inhibitors.Hynes NE et al
169987942006ERBB3 kinase domain mutations are rare in lung, breast and colon carcinomas.Jeong EG et al
200073782009Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3.Jura N et al
218500312012Evidence for two independent associations with type 1 diabetes at the 12q13 locus.Keene KL et al
96931191998Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein.Kim HH et al
166755642006Expression and nuclear localization of ErbB3 in prostate cancer.Koumakpayi IH et al
26878751989Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors.Kraus MH et al
113890772001A naturally occurring secreted human ErbB3 receptor isoform inhibits heregulin-stimulated activation of ErbB2, ErbB3, and ErbB4.Lee H et al
96818221998Isolation and characterization of four alternate c-erbB3 transcripts expressed in ovarian carcinoma-derived cell lines and normal human tissues.Lee H et al
172660422007Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells.Liu B et al
155424352004HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability.Mellinghoff IK et al
153785412004Homozygosity mapping of lethal congenital contractural syndrome type 2 (LCCS2) to a 6 cM interval on chromosome 12q13.Narkis G et al
120451812002c-erbB-3: a nuclear protein in mammary epithelial cells.Offterdinger M et al
108804302000The ErbB signaling network: receptor heterodimerization in development and cancer.Olayioye MA et al
87025721996Neu differentiation factor/neuregulin isoforms activate distinct receptor combinations.Pinkas-Kramarski R et al
13778111992Expression of the c-erbB-3 protein in normal human adult and fetal tissues.Prigent SA et al
172061552007Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3.Sergina NV et al
203512562010ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation.Shi F et al
156880282005Inactivation of ErbB3 by siRNA promotes apoptosis and attenuates growth and invasiveness of human lung adenocarcinoma cell line A549.Sithanandam G et al
82475421993Transcriptional regulation of the c-erbB-3 gene in human breast carcinoma cell lines.Skinner A et al
126484682003ErbBs in mammary development.Stern DF et al
206686832010Genetically dependent ERBB3 expression modulates antigen presenting cell function and type 1 diabetes risk.Wang H et al
224167742012EGFR/HER-targeted therapeutics in ovarian cancer.Wilken JA et al
153141802004Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8.Wu X et al
91273201997High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas.Yi ES et al
167776032006An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.Zhang X et al
155836942005Specificity and heregulin regulation of Ebp1 (ErbB3 binding protein 1) mediated repression of androgen receptor signalling.Zhang Y et al

Other Information

Locus ID:

NCBI: 2065
MIM: 190151
HGNC: 3431
Ensembl: ENSG00000065361


dbSNP: 2065
ClinVar: 2065
TCGA: ENSG00000065361


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
ErbB signaling pathwayKEGGko04012
Calcium signaling pathwayKEGGko04020
ErbB signaling pathwayKEGGhsa04012
Calcium signaling pathwayKEGGhsa04020
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by ERBB2REACTOMER-HSA-1227986
SHC1 events in ERBB2 signalingREACTOMER-HSA-1250196
PI3K events in ERBB2 signalingREACTOMER-HSA-1963642
GRB7 events in ERBB2 signalingREACTOMER-HSA-1306955
Downregulation of ERBB2:ERBB3 signalingREACTOMER-HSA-1358803
Signaling by ERBB4REACTOMER-HSA-1236394
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
ERBB2 Regulates Cell MotilityREACTOMER-HSA-6785631
ERBB2 Activates PTK6 SignalingREACTOMER-HSA-8847993
Signaling by PTK6REACTOMER-HSA-8848021
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
RET signalingREACTOMER-HSA-8853659
Downregulation of ERBB2 signalingREACTOMER-HSA-8863795

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443560Breast NeoplasmsDiseaseClinicalAnnotation, VariantAnnotationassociatedPD30071039
PA448803carboplatinChemicalClinicalAnnotation, VariantAnnotationassociatedPD30071039
PA449383docetaxelChemicalClinicalAnnotation, VariantAnnotationassociatedPD30071039
PA451743trastuzumabChemicalClinicalAnnotation, VariantAnnotationassociatedPD30071039


Pubmed IDYearTitleCitations
174632502007MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.1601
128535642003The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation.347
190739672008Shared and distinct genetic variants in type 1 diabetes and celiac disease.249
186326422008A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy.216
213859432011Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase.194
167290432005Phosphotyrosine interactome of the ErbB-receptor kinase family.193
203512562010ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation.173
121541982002Structure of the extracellular region of HER3 reveals an interdomain tether.131
225522842012MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors.118
235430552013Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3.115


Smita Awasthi ; Anne W Hamburger

ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian))

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

Online version: