Alternative titles; symbols
HGNC Approved Gene Symbol: ERBB3
SNOMEDCT: 715419004;
Cytogenetic location: 12q13.2 Genomic coordinates (GRCh38): 12:56,080,108-56,103,505 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.2 | ?Lethal congenital contractural syndrome 2 | 607598 | Autosomal recessive | 3 |
| {?Erythroleukemia, familial, susceptibility to} | 133180 | Autosomal dominant | 3 | |
| Visceral neuropathy, familial, 1, autosomal recessive | 243180 | Autosomal recessive | 3 |
The ERBB3 gene is a member of the epidermal growth factor receptor tyrosine kinase family (summary by Braunstein et al., 2016).
Kraus et al. (1989) detected a DNA fragment related to but distinct from epidermal growth factor receptor (EGFR; 131550) and ERBB2 (164870). cDNA cloning showed a predicted 148-kD transmembrane polypeptide with structural features identifying it as a member of the ERBB gene family, prompting the designation ERBB3. Markedly elevated ERBB3 mRNA levels were demonstrated in certain human mammary tumor cell lines, suggesting that it may play a role in some human malignancies just as does EGFR (also called ERBB1).
Le et al. (2021) reviewed human scRNA-seq datasets and observed low or undetectable expression of ERBB3 in the intestinal muscle cell population. In mouse, enteric nervous system (ENS) scRNA-seq datasets from embryonic day (E) 15.5 and E18.5 showed expression almost exclusively in the enteric progenitor and glial cell populations. Low or absent expression was found in neurons. The authors suggested that the impact of ERBB3 variants might be cell autonomous in the ENS and non-cell autonomous in intestinal smooth muscle.
By in situ hybridization, Kraus et al. (1989) mapped the ERBB3 gene to chromosome 12q13.
Cho and Leahy (2002) determined the 2.6-angstrom crystal structure of the entire extracellular region of human HER3. The structure consists of 4 domains with structural homology to domains found in the type I insulin-like growth factor receptor (147370). The HER3 structure revealed a contact between domains II and IV that constrains the relative orientations of ligand-binding domains and provides a structural basis for understanding both multiple-affinity forms of EGFRs and conformational changes induced in the receptor by ligand binding during signaling.
Epidermal growth factor (131530), transforming growth factor alpha (190170), and amphiregulin (104640) are structurally and functionally related growth regulatory proteins. They all are secreted polypeptides that bind to the 170-kD cell-surface EGF receptor, activating its intrinsic kinase activity. Plowman et al. (1990) speculated that these 3 proteins may differentially interact with a homolog of EGFR. They failed to show any interaction between these 3 secreted growth factors and ERBB2, a known EGFR-related protein. Searching for other members of this family of receptor tyrosine kinases, however, they cloned and studied the expression of ERBB3, which they referred to as HER3. The cDNA was isolated from a human carcinoma cell line, and its 6-kb transcript was identified in various human tissues.
Carraway et al. (1994) demonstrated that ERBB3 is a receptor for heregulin (HGL; see NRG1, 142445) and is capable of mediating HGL-stimulated tyrosine phosphorylation of itself.
By immunoprecipitation analysis, Diamonti et al. (2002) showed that NRDP1 (RNF41; 620051) interacted specifically with the ERBB3 and ERBB4 (600543) receptors, with the interaction independent of the receptor activation state. When coexpressed in COS7 cells, NRDP1 and ERBB3 colocalized extensively, and NRDP1 expression specifically induced redistribution of ERBB3 from the cell surface to intracellular NRDP1-containing compartments. Further analysis indicated that NRDP1 induced suppression of ERBB3 and ERBB4 receptor levels in COS7 cells. A polypeptide corresponding to the C-terminal 183 amino acids of human NRDP1 interfered with ERBB3 removal and potentiated neuregulin signaling in MCF7 cells by acting as a dominant-negative inhibitor of the NRDP1-mediated process.
Qiu and Goldberg (2002) identified human NRDP1 as an E3 ubiquitin ligase that ubiquitinated ERBB3 for its degradation before it exited from the endoplasmic reticulum. NRDP1 interacted with ERBB3 through its C-terminal half and ubiquitinated ERBB3 in the presence of UBCH5 (UBE2D1; 602961). NRDP1-mediated ERBB3 degradation appeared to be independent of either ERBB3 heterodimerization or ligand stimulation. Mutation analysis showed that the RING finger domain of NRDP1 was critical for ERBB3 ubiquitination and degradation.
Memon et al. (2004) used real-time PCR to quantify expression of NRG1, NRG2 (603818), NRG3 (605533), and NRG4 (610894) and their receptors HER3 and HER4 (ERBB4; 600543) in biopsies from 88 bladder cancer patients. They detected NRG4 expression in 91% of bladder cancer cases, with significantly lower expression in biopsies of superficial invasive tumors in comparison to superficial tumors, indicating early loss of NRG4 expression during bladder cancer progression. NRG4 downregulation was strongly correlated with stage, grade, and type of tumor. Increased expression of HER3, HER4, and NRG4 correlated to better survival. Coexpression of HER3 and HER4 with NRG4 showed even better correlation with survival (p = 0.0034 and p = 0.0080, respectively).
Jones et al. (2006) used microarrays comprising virtually every Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domain encoded in the human genome to measure the equilibrium dissociation constant of each domain for 61 peptides representing physiologic sites of tyrosine phosphorylation on the 4 ErbB receptors. By slicing through the network at different affinity thresholds, Jones et al. (2006) found surprising differences between the receptors. Most notably, EGFR and ErbB2 became markedly more promiscuous as the threshold was lowered, whereas ErbB3 did not. Because EGFR and ErbB2 are overexpressed in many human cancers, Jones et al. (2006) concluded that the extent to which promiscuity changes with protein concentration may contribute to the oncogenic potential of receptor tyrosine kinases.
In lung cancer specimens that had developed resistance to gefitinib, Engelman et al. (2007) found that amplification of MET (164860) caused gefitinib resistance by driving ERBB3-dependent activation of phosphoinositide 3-kinase, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, Engelman et al. (2007) proposed that MET amplification may promote drug resistance in other ERBB-driven cancers as well.
Early social isolation results in adult behavioral and cognitive dysfunction that correlates with white matter alterations. Makinodan et al. (2012) showed that mice isolated for 2 weeks immediately after weaning have alterations in prefrontal cortex function and myelination that do not recover with reintroduction into a social environment. These alterations, which occur only during this critical period, are phenocopied by loss of oligodendrocyte ErbB3 receptors, and social isolation leads to reduced expression of the ErbB3 ligand neuregulin-1 (NRG1; 142445). Makinodan et al. (2012) concluded that social experience regulates prefrontal cortex myelination through neuregulin-1/ErbB3 signaling and that this is essential for normal cognitive function, thus providing a cellular and molecular context to understand the consequences of social isolation.
Lethal Congenital Contracture Syndrome Type 2
Lethal congenital contracture syndrome type 2 (LCCS2; 607598), a neonatally lethal form of arthrogryposis, originally described in 2 Israeli Bedouin kindreds, is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of markedly distended urinary bladder. Narkis et al. (2007) showed that the disorder is caused by aberrant splicing of ERBB3, which leads to a predicted truncated protein. ERBB3, an activator of the phosphatidylinositol-3-kinase/Akt pathway, which regulates cell survival and vesicle trafficking, is essential for the generation of precursors of Schwann cells that normally accompany peripheral axons of motor neurons. Gain-of-function mutations in members of the epidermal growth factor tyrosine kinase receptor family are associated with predilection to cancer; see ERBB2 (164870). This was the first report of a human phenotype resulting from loss of function of a member of this group. The human disorder is reminiscent of the phenotype of the null mutant of this mouse ortholog. Most Erbb3-knockout embryos die before birth, without Schwann cell precursors and Schwann cells that normally accompany peripheral axons of sensory and motor neurons.
Susceptibility to Familial Erythroleukemia
In 2 living affected members of the family with familial erythroleukemia (133180) originally described by Nissenblatt et al. (1982) and Lee et al. (1987), Braunstein et al. (2016) identified a heterozygous missense mutation in the ERBB3 gene (A1337T; 190151.0002). The mutation was also found in a 63-year-old asymptomatic family member, indicating incomplete penetrance, and in a woman who died of metastatic breast cancer, but who did not have leukemia. In vitro functional studies indicated that the mutation resulted in increased cellular proliferation under certain circumstances.
Visceral Neuropathy 1, Autosomal Recessive
In 6 affected individuals from 4 unrelated families with visceral neuropathy (VSCN1; 243180), Le et al. (2021) identified biallelic missense or frameshift mutations in the ERBB3 gene (see, e.g., 190151.0003-190151.0005) that segregated with disease and were not found in the gnomAD database. Functional analysis demonstrated reduced expression and partial or total loss of function for the ERBB3 frameshift and missense mutations, respectively.
Associations Pending Confirmation
The Wellcome Trust Case Control Consortium (2007) reported an association between rs2292239 in the ERBB3 gene and type 1 diabetes (222100) (p = 1.49 x 10(-9); OR, 1.30). In a study of 4,000 individuals with type 1 diabetes, 5,000 controls, and 2,997 family trios independent of the Wellcome Trust Case Control Consortium (2007) study, Todd et al. (2007) confirmed the previously reported association of rs2292239 (p = 3.83 x 10(-16); combined with WTCCC p = 1.52 x 10(-20)).
Barrett et al. (2009) reported the findings of a genomewide association study of type 1 diabetes, combined in a metaanalysis with 2 previously published studies (Wellcome Trust Case Control Consortium, 2007; Cooper et al., 2008). The total sample set included 7,514 cases and 9,045 reference samples. Using an analysis that combined comparisons over the 3 studies, they confirmed several previously reported associations, including rs2292239 at 12q13.2 (p = 2.2 x 10(-25)).
Le et al. (2021) evaluated gut muscle development in neural crest-specific Erbb3-deficient mice. Histologic analysis and immunohistochemistry revealed hypoganglionosis, but no gross alteration of the 2 muscle layers in mutants compared to controls at embryonic day 17.5. The authors concluded that invalidation of Erbb3 in neural crest cells does not impact the intestinal smooth muscle, at least before birth.
In all affected members of a large Israeli Bedouin family with lethal congenital contracture syndrome type 2 (LCCS2; 607598), and in an affected individual from another family, Narkis et al. (2007) found a homozygous A-to-G substitution 8 basepairs 5-prime of exon 11 of the ERBB3 gene (IVS10-8A-G). The mutation caused an insertion of 8 basepairs between exons 10 and 11 and resulted in frameshift and premature termination, generating a 399-amino acid protein instead of the native 1,341 amino acids.
In 2 members of a family with familial erythroleukemia (FERLK; 133180), Braunstein et al. (2016) identified a heterozygous c.4009G-A transition in the ERBB3 gene, resulting in an ala1337-to-thr (A1337T) substitution at a conserved residue near the C terminus. The mutation, which was found by whole-exome sequencing, was not found in the Exome Variant Server, but was found at a low frequency in the ExAC database (7 of 119,654 alleles). The variant was also found in an asymptomatic 63-year-old family member, indicating incomplete penetrance, as well as in a female family member who died from metastatic breast cancer, but did not have leukemia. The family had a significant history of various solid tumors. Expression of the mutation into murine pro-B cells (BaF3) and human hematopoietic progenitor cells caused a growth advantage and resulted in increased cellular proliferation compared to wildtype. However, the increased proliferation was observed only in the presence of ERBB2 (164870), NRG1B (see 142445), and EPO (133170), indicating that the growth was dependent on ligand binding and heterodimerization. Analysis of the cell cycle under these conditions showed a decrease in the G1 phase and an increase in the S and G2/M phase in cells carrying the mutation compared to controls. These findings suggested that the A1337T variant overcomes a G1 phase cell cycle block. Cells carrying the mutation also showed a block in erythroid differentiation compared to controls.
In a 15-year-old French boy (F1:II-3) with visceral neuropathy (VSCN1; 243180), Le et al. (2021) identified compound heterozygosity for a c.2359A-C transversion (c.2359A-C, NM_001982.3), resulting in a thr787-to-pro (T787P) substitution, and a c.2695G-A transition, resulting in a val899-to-met (V899M; 190151.0004) substitution, both at highly conserved residues within the pseudokinase domain. The mutations were detected by trio whole-exome sequencing, and Sanger sequencing confirmed heterozygosity for 1 of the mutations in each of his unaffected parents. Western blot analysis of transfected Neuro-2a cells revealed an almost total absence of phosphorylation of the T787P and V899M mutants, with or without NRG1 (142445).
For discussion of the c.2695G-A transition (c.2695G-A, NM_001982.3) in the ERBB3 gene, resulting in a val899-to-met (V899M) substitution, that was found in compound heterozygous state in a 15-year-old French boy (F1:II-3) with visceral neuropathy (VSCN1; 243180) by Le et al. (2021), see 190151.0003.
In an Egyptian brother and sister (F2:II-2 and F2:II-3) with visceral neuropathy (VSCN1; 243180), Le et al. (2021) identified homozygosity for a 1-bp deletion (c.3297delG, NM_001982.3) in the ERBB3 gene, causing a frameshift predicted to result in a premature termination codon (His1100MetfsTer2). The deletion was detected by trio whole-exome sequencing, and Sanger sequencing confirmed the deletion and expected segregation in the family. RT-qPCR on patient fibroblasts confirmed that ERBB3 mRNA was significantly lower than in cells from the mother and from a control.
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Braunstein, E. M., Li, R., Sobreira, N., Marosy, B., Hetrick, K., Doheny, K., Gocke, C. D., Valle, D., Brodsky, R. A., Cheng, L. A germline ERBB3 variant is a candidate for predisposition to erythroid MDS/erythroleukemia. (Letter) Leukemia 30: 2242-2245, 2016. [PubMed: 27416908] [Full Text: https://doi.org/10.1038/leu.2016.173]
Carraway, K. L., III, Sliwkowski, M. X., Akita, R., Platko, J. V., Guy, P. M., Nuijens, A., Diamonti, A. J., Vandlen, R. L., Cantley, L. C., Cerione, R. A. The erbB3 gene product is a receptor for heregulin. J. Biol. Chem. 269: 14303-14306, 1994. [PubMed: 8188716]
Cho, H.-S., Leahy, D. J. Structure of the extracellular region of HER3 reveals an interdomain tether. Science 297: 1330-1333, 2002. [PubMed: 12154198] [Full Text: https://doi.org/10.1126/science.1074611]
Cooper, J. D., Smyth, D. J., Smiles, A. M., Plagnol, V., Walker, N. M., Allen, J. E., Downes, K., Barrett, J. C., Healy, B. C., Mychaleckyj, J. C., Warram, J. H., Todd, J. A. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nature Genet. 40: 1399-1401, 2008. [PubMed: 18978792] [Full Text: https://doi.org/10.1038/ng.249]
Diamonti, A. J., Guy, P. M., Ivanof, C., Wong, K., Sweeney, C., Carraway, K. L. An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels. Proc. Nat. Acad. Sci. 99: 2866-2871, 2002. [PubMed: 11867753] [Full Text: https://doi.org/10.1073/pnas.052709799]
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., Kosaka, T., Holmes, A. J., Rogers, A. M., Cappuzzo, F., Mok, T., Lee, C., Johnson, B. E., Cantley, L. C., Janne, P. A. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316: 1039-1043, 2007. [PubMed: 17463250] [Full Text: https://doi.org/10.1126/science.1141478]
Jones, R. B., Gordus, A., Krall, J. A., MacBeath, G. A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 439: 168-174, 2006. [PubMed: 16273093] [Full Text: https://doi.org/10.1038/nature04177]
Kraus, M. H., Issing, W., Miki, T., Popescu, N. C., Aaronson, S. A. Isolation 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. Proc. Nat. Acad. Sci. 86: 9193-9197, 1989. [PubMed: 2687875] [Full Text: https://doi.org/10.1073/pnas.86.23.9193]
Le, T.-L., Galmiche, L., Levy, J., Suwannarat, P., Hellebrekers, D. M. E. I., Morarach, K., Boismoreau, F., Theunissen, T. E. J., Lefebvre, M., Pelet, A., Martinovic, J., Gelot, A., and 25 others. Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans. J. Clin. Invest. 131: e145837, 2021. [PubMed: 33497358] [Full Text: https://doi.org/10.1172/JCI145837]
Lee, E. J., Schiffer, C. A., Misawa, S., Testa, J. R. Clinical and cytogenetic features of familial erythroleukaemia. Brit. J. Haemat. 65: 313-320, 1987. [PubMed: 3471269] [Full Text: https://doi.org/10.1111/j.1365-2141.1987.tb06859.x]
Makinodan, M., Rosen, K. M., Ito, S., Corfas, G. A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 337: 1357-1360, 2012. [PubMed: 22984073] [Full Text: https://doi.org/10.1126/science.1220845]
Memon, A. A., Sorensen, B. S., Melgard, P., Fokdal, L., Thykjaer, T., Nexo, E. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Brit. J. Cancer 91: 2034-2041, 2004. [PubMed: 15583696] [Full Text: https://doi.org/10.1038/sj.bjc.6602251]
Narkis, G., Ofir, R., Manor, E., Landau, D., Elbedour, K., Birk, O. S. Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway. Am. J. Hum. Genet. 81: 589-595, 2007. [PubMed: 17701904] [Full Text: https://doi.org/10.1086/520770]
Nissenblatt, M. J., Bias, W., Borgaonkar, D., Dixon, S., Cody, R. P. Familial erythroleukemia: four cases of the Diguglielmo syndrome in close relatives. Johns Hopkins Med. J. 150: 1-9, 1982. [PubMed: 6948132]
Plowman, G. D., Whitney, G. S., Neubauer, M. G., Green, J. M., McDonald, V. L., Todaro, G. J., Shoyab, M. Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proc. Nat. Acad. Sci. 87: 4905-4909, 1990. [PubMed: 2164210] [Full Text: https://doi.org/10.1073/pnas.87.13.4905]
Qiu, X. B., Goldberg, A. L. Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3. Proc. Nat. Acad. Sci. 99: 14843-14848, 2002. Note: Erratum: Proc. Nat. Acad. Sci. 99: 17221 only, 2002. [PubMed: 12411582] [Full Text: https://doi.org/10.1073/pnas.232580999]
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Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661-678, 2007. [PubMed: 17554300] [Full Text: https://doi.org/10.1038/nature05911]