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Gene Review

ERBB3  -  erb-b2 receptor tyrosine kinase 3

Homo sapiens

Synonyms: ErbB-3, HER3, LCCS2, MDA-BF-1, Proto-oncogene-like protein c-ErbB-3, ...
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Disease relevance of ERBB3


High impact information on ERBB3


Chemical compound and disease context of ERBB3


Biological context of ERBB3

  • We found the avian erythroblastic leukemia viral oncogene homologue 3 (ERBB3) to be one of the most dramatically up-regulated genes in CCSST [1].
  • In conclusion, our data demonstrate new aspects of the phenotype and the biological behavior of CCSST and reveal ERBB3 to be a useful diagnostic marker [1].
  • Application of nonparametric Wilcoxon statistical analyses (P < 1 x 10(-6)) and the criteria of 1.5-fold differential gene expression change resulted in the identification of 218 genes, including BMI-1, ERBB3, and those involved in the ubiquitin-proteasome pathway [17].
  • This has been attributed to the disruption of ERBB3/ERBB2 heterodimers that maintain a crucial cell survival signal via phosphatidylinositol 3-kinase/AKT [18].
  • Overexpression of ERBB3 appears to result from increased levels of gene transcription since in none of the cell lines or primary cancers analysed did we find evidence of gene amplification [2].

Anatomical context of ERBB3


Associations of ERBB3 with chemical compounds

  • We conclude that ErbB2 and ErbB3 are expressed in T(84) cells and are functionally coupled to inhibition of calcium-dependent chloride secretion [22].
  • We tested this hypothesis using bleomycin lung injury of transgenic mice incapable of signaling through HER2/HER3 due to lung-specific dominant-negative HER3 (DNHER3) expression [23].
  • In fact, abundant ErbB-3 expression is detected only in gefitinib-sensitive NSCLC cell lines [12].
  • While EGF, transforming growth factor (TGF)-alpha, and amphiregulin only had a moderate effect, NDF dramatically increased the ErbB-3 phosphotyrosine content [24].
  • Binding interaction of the heregulinbeta egf domain with ErbB3 and ErbB4 receptors assessed by alanine scanning mutagenesis [25].

Physical interactions of ERBB3

  • These data show that the linear N-terminal region of EGF-like growth factors is directly involved in binding to ErbB-3 [26].
  • Previous biophysical studies suggest that the ErbB3 extracellular region remains monomeric when bound to NRG [27].
  • Using the yeast two-hybrid system, we have isolated an ErbB-3 binding protein (Ebp1) that interacts with the juxtamembrane domain of ErbB-3 [28].
  • We also show that the binding of neuregulin-1beta to ErbB4 and ErbB3 and the binding of betacellulin to both ErbB4 and ErbB1 does not decrease at low pH, unlike the binding of epidermal growth factor and transforming growth factor-alpha to ErbB1 [29].
  • We conclude that ErbB-3 is used to couple EGFR to the PI3K/Akt pathway in gefitinib-sensitive NSCLC cell lines harboring WT and mutant EGFRs [12].

Regulatory relationships of ERBB3

  • RESULTS: Our results demonstrate that NRG activates ErbB-2/ErbB-3 heterodimers and induces cell death of LNCaP cells [30].
  • Furthermore, EGF- and BTC-induced activation of ErbB-3 is impaired in the absence of ErbB-2, suggesting that ErbB-2 has a role in the lateral transmission of signals between other ErbB receptors [31].
  • By reverse transcription polymerase chain reaction and Western blotting, we found that the breast cells also express HER3 and that the ovarian line co-expresses the HER4 message [32].
  • Our results suggest that the final outcome of patients with high HER1- and HER2-expressing tumours depends on the expression of HER3 and HER4 [33].
  • Neither EGF nor heregulin (HRG) induced c-erbB2/c-erbB3 receptor complexes in BT474 [34].

Other interactions of ERBB3

  • These findings suggest that increased ERBB3 expression, as in the case of epidermal growth factor receptor and ERBB2, may play a role in some human malignancies [19].
  • All primary tumors examined expressed readily detectable levels of HER1 and HER3 and lower levels of HER2 and HER4 [35].
  • This sequence-independent effect of the N-terminal domain correlates with an enhanced ability of full-size neuregulin 1 to disrupt higher order oligomers of the ERBB3 extracellular domains in vitro [36].
  • However, compared with epidermal growth factor (EGF) receptor, the ERBB2/ERBB3 signaling pair is considered to be attenuation-deficient [36].
  • Immunoprecipitation experiments revealed that gp130 was constitutively associated with ErbB-2 and ErbB-3 [37].

Analytical, diagnostic and therapeutic context of ERBB3

  • In this report we demonstrate by nucleic acid analysis and immunohistochemistry that the recently recognised third member of this gene family, ERBB3, shows a wide range of expression in breast cancer, and shows stronger immunoreactivity than that observed in normal tissue in 43 out of 195 cases (22%) of primary breast cancer [2].
  • We have examined the expression of the two ERBB3 transcripts by Northern blotting in cancer cell lines and normal human fetal and adult tissues [38].
  • In a former microarray expression study, we identified ERBB3, a member of the epidermal growth factor receptor (EGFR) family, as a promising new diagnostic marker in the differential diagnosis of CCSST [39].
  • Schizophrenia is not associated with the functional candidate gene ERBB3: Results from a case-control study [40].
  • We used in situ hybridization to show that normal epidermal cells produce heregulin-alpha messenger RNA and that heregulin receptors, HER3 and/or HER4, as well as their coreceptor HER2/NEU, are expressed by Paget cells [41].


  1. Expression profiling of t(12;22) positive clear cell sarcoma of soft tissue cell lines reveals characteristic up-regulation of potential new marker genes including ERBB3. Schaefer, K.L., Brachwitz, K., Wai, D.H., Braun, Y., Diallo, R., Korsching, E., Eisenacher, M., Voss, R., Van Valen, F., Baer, C., Selle, B., Spahn, L., Liao, S.K., Lee, K.A., Hogendoorn, P.C., Reifenberger, G., Gabbert, H.E., Poremba, C. Cancer Res. (2004) [Pubmed]
  2. Expression of the ERBB3 gene product in breast cancer. Lemoine, N.R., Barnes, D.M., Hollywood, D.P., Hughes, C.M., Smith, P., Dublin, E., Prigent, S.A., Gullick, W.J., Hurst, H.C. Br. J. Cancer (1992) [Pubmed]
  3. Expression of c-erbB family gene products in adenoid cystic carcinoma of salivary glands: an immunohistochemical study. Shintani, S., Funayama, T., Yoshihama, Y., Alcalde, R.E., Ootsuki, K., Terakado, N., Matsumura, T. Anticancer Res. (1995) [Pubmed]
  4. Prognostic significance of ERBB3 overexpression in oral squamous cell carcinoma. Shintani, S., Funayama, T., Yoshihama, Y., Alcalde, R.E., Matsumura, T. Cancer Lett. (1995) [Pubmed]
  5. A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells. Chen, N., Ye, X.C., Chu, K., Navone, N.M., Sage, E.H., Yu-Lee, L.Y., Logothetis, C.J., Lin, S.H. Cancer Res. (2007) [Pubmed]
  6. HER3 is a determinant for poor prognosis in melanoma. Reschke, M., Mihic-Probst, D., van der Horst, E.H., Knyazev, P., Wild, P.J., Hutterer, M., Meyer, S., Dummer, R., Moch, H., Ullrich, A. Clin. Cancer Res. (2008) [Pubmed]
  7. High expression of HER3 is associated with a decreased survival in gastric cancer. Hayashi, M., Inokuchi, M., Takagi, Y., Yamada, H., Kojima, K., Kumagai, J., Kawano, T., Sugihara, K. Clin. Cancer Res. (2008) [Pubmed]
  8. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Qiu, Y., Ravi, L., Kung, H.J. Nature (1998) [Pubmed]
  9. Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Carraway, K.L., Weber, J.L., Unger, M.J., Ledesma, J., Yu, N., Gassmann, M., Lai, C. Nature (1997) [Pubmed]
  10. Ligands for ErbB-family receptors encoded by a neuregulin-like gene. Chang, H., Riese, D.J., Gilbert, W., Stern, D.F., McMahan, U.J. Nature (1997) [Pubmed]
  11. c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Levkowitz, G., Waterman, H., Zamir, E., Kam, Z., Oved, S., Langdon, W.Y., Beguinot, L., Geiger, B., Yarden, Y. Genes Dev. (1998) [Pubmed]
  12. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Engelman, J.A., Jänne, P.A., Mermel, C., Pearlberg, J., Mukohara, T., Fleet, C., Cichowski, K., Johnson, B.E., Cantley, L.C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. Neuroglycan C, a novel member of the neuregulin family. Kinugasa, Y., Ishiguro, H., Tokita, Y., Oohira, A., Ohmoto, H., Higashiyama, S. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  14. Inhibition of ErbB-2 and ErbB-3 expression by quercetin prevents transforming growth factor alpha (TGF-alpha)- and epidermal growth factor (EGF)-induced human PC-3 prostate cancer cell proliferation. Huynh, H., Nguyen, T.T., Chan, E., Tran, E. Int. J. Oncol. (2003) [Pubmed]
  15. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Knuefermann, C., Lu, Y., Liu, B., Jin, W., Liang, K., Wu, L., Schmidt, M., Mills, G.B., Mendelsohn, J., Fan, Z. Oncogene (2003) [Pubmed]
  16. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Erjala, K., Sundvall, M., Junttila, T.T., Zhang, N., Savisalo, M., Mali, P., Kulmala, J., Pulkkinen, J., Grenman, R., Elenius, K. Clin. Cancer Res. (2006) [Pubmed]
  17. Identification of discriminators of hepatoma by gene expression profiling using a minimal dataset approach. Neo, S.Y., Leow, C.K., Vega, V.B., Long, P.M., Islam, A.F., Lai, P.B., Liu, E.T., Ren, E.C. Hepatology (2004) [Pubmed]
  18. Medulloblastoma sensitivity to 17-allylamino-17-demethoxygeldanamycin requires MEK/ERKM. Calabrese, C., Frank, A., Maclean, K., Gilbertson, R. J. Biol. Chem. (2003) [Pubmed]
  19. 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. Kraus, M.H., Issing, W., Miki, T., Popescu, N.C., Aaronson, S.A. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  20. Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. Aston, C., Jiang, L., Sokolov, B.P. Mol. Psychiatry (2005) [Pubmed]
  21. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Amin, D.N., Hida, K., Bielenberg, D.R., Klagsbrun, M. Cancer Res. (2006) [Pubmed]
  22. ErbB2 and ErbB3 receptors mediate inhibition of calcium-dependent chloride secretion in colonic epithelial cells. Keely, S.J., Barrett, K.E. J. Biol. Chem. (1999) [Pubmed]
  23. Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice. Nethery, D.E., Moore, B.B., Minowada, G., Carroll, J., Faress, J.A., Kern, J.A. J. Appl. Physiol. (2005) [Pubmed]
  24. Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. Beerli, R.R., Hynes, N.E. J. Biol. Chem. (1996) [Pubmed]
  25. Binding interaction of the heregulinbeta egf domain with ErbB3 and ErbB4 receptors assessed by alanine scanning mutagenesis. Jones, J.T., Ballinger, M.D., Pisacane, P.I., Lofgren, J.A., Fitzpatrick, V.D., Fairbrother, W.J., Wells, J.A., Sliwkowski, M.X. J. Biol. Chem. (1998) [Pubmed]
  26. Role of the N-terminus of epidermal growth factor in ErbB-2/ErbB-3 binding studied by phage display. Stortelers, C., Souriau, C., van Liempt, E., van de Poll, M.L., van Zoelen, E.J. Biochemistry (2002) [Pubmed]
  27. ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. Berger, M.B., Mendrola, J.M., Lemmon, M.A. FEBS Lett. (2004) [Pubmed]
  28. Interaction of the PA2G4 (EBP1) protein with ErbB-3 and regulation of this binding by heregulin. Yoo, J.Y., Wang, X.W., Rishi, A.K., Lessor, T., Xia, X.M., Gustafson, T.A., Hamburger, A.W. Br. J. Cancer (2000) [Pubmed]
  29. The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Bouyain, S., Longo, P.A., Li, S., Ferguson, K.M., Leahy, D.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  30. Neuregulin promotes autophagic cell death of prostate cancer cells. Tal-Or, P., Di-Segni, A., Lupowitz, Z., Pinkas-Kramarski, R. Prostate (2003) [Pubmed]
  31. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. Graus-Porta, D., Beerli, R.R., Daly, J.M., Hynes, N.E. EMBO J. (1997) [Pubmed]
  32. Heregulin activation of extracellular acidification in mammary carcinoma cells is associated with expression of HER2 and HER3. Chan, S.D., Antoniucci, D.M., Fok, K.S., Alajoki, M.L., Harkins, R.N., Thompson, S.A., Wada, H.G. J. Biol. Chem. (1995) [Pubmed]
  33. The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients. Memon, A.A., Sorensen, B.S., Meldgaard, P., Fokdal, L., Thykjaer, T., Nexo, E. Br. J. Cancer (2006) [Pubmed]
  34. Epidermal growth factor receptor, c-erbB2 and c-erbB3 receptor interaction, and related cell cycle kinetics of SK-BR-3 and BT474 breast carcinoma cells. Brockhoff, G., Heiss, P., Schlegel, J., Hofstaedter, F., Knuechel, R. Cytometry. (2001) [Pubmed]
  35. Proliferation of human neuroblastomas mediated by the epidermal growth factor receptor. Ho, R., Minturn, J.E., Hishiki, T., Zhao, H., Wang, Q., Cnaan, A., Maris, J., Evans, A.E., Brodeur, G.M. Cancer Res. (2005) [Pubmed]
  36. The N-terminal Domains of Neuregulin 1 Confer Signal Attenuation. Warren, C.M., Kani, K., Landgraf, R. J. Biol. Chem. (2006) [Pubmed]
  37. An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. Grant, S.L., Hammacher, A., Douglas, A.M., Goss, G.A., Mansfield, R.K., Heath, J.K., Begley, C.G. Oncogene (2002) [Pubmed]
  38. Intracellular expression of the truncated extracellular domain of c-erbB-3/HER3. Srinivasan, R., Leverton, K.E., Sheldon, H., Hurst, H.C., Sarraf, C., Gullick, W.J. Cell. Signal. (2001) [Pubmed]
  39. Constitutive activation of neuregulin/ERBB3 signaling pathway in clear cell sarcoma of soft tissue. Schaefer, K.L., Brachwitz, K., Braun, Y., Diallo, R., Wai, D.H., Zahn, S., Schneider, D.T., Kuhnen, C., Vollmann, A., Brockhoff, G., Gabbert, H.E., Poremba, C. Neoplasia (2006) [Pubmed]
  40. Schizophrenia is not associated with the functional candidate gene ERBB3: Results from a case-control study. Kanazawa, T., Glatt, S.J., Tsutsumi, A., Kikuyama, H., Koh, J., Yoneda, H., Tsuang, M.T. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2007) [Pubmed]
  41. Pathogenesis of Paget's disease: epidermal heregulin-alpha, motility factor, and the HER receptor family. Schelfhout, V.R., Coene, E.D., Delaey, B., Thys, S., Page, D.L., De Potter, C.R. J. Natl. Cancer Inst. (2000) [Pubmed]
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