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Gene Review

ERBB4  -  erb-b2 receptor tyrosine kinase 4

Homo sapiens

Synonyms: ALS19, HER4, Proto-oncogene-like protein c-ErbB-4, Receptor tyrosine-protein kinase erbB-4, Tyrosine kinase-type cell surface receptor HER4, ...
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Disease relevance of ERBB4

  • To determine the functional significance of 4ICD nuclear translocation in a physiologically relevant system, we have demonstrated that cotransfection of ERBB4 and STAT5A in a human breast cancer cell line stimulates beta-casein promoter activity [1].
  • Significantly, ERBB4-CA potentiated the proapoptotic function of ERBB4 in each breast, prostate and ovarian cancer cell line tested [2].
  • We detected the ERBB4 somatic mutations in 3 of 180 gastric carcinomas (1.7%), 3 of 104 colorectal carcinomas (2.9%), 5 of 217 nonsmall cell lung cancers (2.3%) and 1 of 94 breast carcinomas (1.1%) [3].
  • CONCLUSION: We hypothesise that: (i) ERBB4 is important for differentiation in NU; (ii) ERBB2 is up-regulated with carcinogenesis in the urinary bladder but does not discriminate between bladder cancer with or without metastases; (iii) EGFR may be a marker of indolent disease [4].
  • In contrast, the lack of HER-4 expression might increase the metastatic capacity of pancreatic cancer cells [5].

High impact information on ERBB4


Chemical compound and disease context of ERBB4


Biological context of ERBB4

  • Clinically, cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression [8].
  • Our recent data suggests that regulation of gene expression by the ERBB4 nuclear protein and the proapoptotic activity of ERBB4 involves the gamma-secretase release of 4ICD [13].
  • The 12 ERBB4 mutations consisted of 1 in-frame duplication mutation and 8 missense mutations in the exons, and 3 mutations in the introns [3].
  • In contrast, the phenotypes of transgenic mice expressing dominant negative ERBB2 and ERBB4 proteins suggest that these receptors differentially act to promote or maintain alveolar differentiation [14].
  • On the other hand, HB-EGF is not a mitogen for cells expressing HER4, in contrast to its ability to stimulate both chemotaxis and proliferation in cells expressing HER1 [15].

Anatomical context of ERBB4


Associations of ERBB4 with chemical compounds


Physical interactions of ERBB4


Co-localisations of ERBB4

  • HB-EGF colocalized with HER-1 and HER-4 in HPMCs and induced their adhesion to collagen type I, expression of beta 1 integrins, and migration [24].

Regulatory relationships of ERBB4

  • Functionally, ERBB4-CA exhibited higher levels of nuclear translocation than wild-type ERBB4, leading to significantly enhanced ERBB4-induced STAT5A simulation of the beta-casein promoter [2].
  • Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities [13].
  • 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 [25].
  • In contrast, the ovarian cells expressing high levels of HER2 and low levels of HER4 or CHO-K1 and 293-EBNA cells expressing HER2 alone were not responsive to heregulin [25].
  • CONCLUSIONS: HB-EGF may play a vital role in regulating luteal growth in a juxtacrine manner and through activating HER4 signalling [26].

Other interactions of ERBB4

  • This report describes the isolation and recombinant expression of a cDNA clone encoding HER4, the fourth member of the human epidermal growth factor receptor (EGFR) family [17].
  • We found a positive correlation between ERBB3 and ERBB4 mRNA levels, and a negative correlation between the expression of these 2 latter genes and that of ERBB1 [27].
  • In the normal breast, ERBB4 regulates epithelial differentiation and functions as a nuclear chaperone for signal transducer and activator of transcription (STAT) 5A, thereby stimulating milk-gene expression [2].
  • Here, we performed mutational analysis of the ERBB4 kinase domain by polymerase chain reaction-single-strand conformation polymorphism assay in 595 cancer tissues from stomach, lung, colon and breast [3].
  • Since limited information exists concerning the expression of other parts of the EGF system, we examined the expression of the receptors HER3 and HER4 and their activating ligands, the heregulins (HRGs), in bladder cancer patients [28].

Analytical, diagnostic and therapeutic context of ERBB4


  1. The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone. Williams, C.C., Allison, J.G., Vidal, G.A., Burow, M.E., Beckman, B.S., Marrero, L., Jones, F.E. J. Cell Biol. (2004) [Pubmed]
  2. A constitutively active ERBB4/HER4 allele with enhanced transcriptional coactivation and cell-killing activities. Vidal, G.A., Clark, D.E., Marrero, L., Jones, F.E. Oncogene (2007) [Pubmed]
  3. Somatic mutations of the ERBB4 kinase domain in human cancers. Soung, Y.H., Lee, J.W., Kim, S.Y., Wang, Y.P., Jo, K.H., Moon, S.W., Park, W.S., Nam, S.W., Lee, J.Y., Yoo, N.J., Lee, S.H. Int. J. Cancer (2006) [Pubmed]
  4. Expression of the epidermal growth factor receptor family in normal and malignant urothelium. Røtterud, R., Nesland, J.M., Berner, A., Fosså, S.D. BJU international. (2005) [Pubmed]
  5. Comparative analysis of the EGF-receptor family in pancreatic cancer: expression of HER-4 correlates with a favourable tumor stage. Thybusch-Bernhardt, A., Beckmann, S., Juhl, H. International journal of surgical investigation. (2001) [Pubmed]
  6. Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Plowman, G.D., Green, J.M., Culouscou, J.M., Carlton, G.W., Rothwell, V.M., Buckley, S. Nature (1993) [Pubmed]
  7. 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]
  8. The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Naresh, A., Long, W., Vidal, G.A., Wimley, W.C., Marrero, L., Sartor, C.I., Tovey, S., Cooke, T.G., Bartlett, J.M., Jones, F.E. Cancer Res. (2006) [Pubmed]
  9. Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor. Culouscou, J.M., Plowman, G.D., Carlton, G.W., Green, J.M., Shoyab, M. J. Biol. Chem. (1993) [Pubmed]
  10. Coregulation of Estrogen Receptor by ERBB4/HER4 Establishes a Growth-Promoting Autocrine Signal in Breast Tumor Cells. Zhu, Y., Sullivan, L.L., Nair, S.S., Williams, C.C., Pandey, A.K., Marrero, L., Vadlamudi, R.K., Jones, F.E. Cancer Res. (2006) [Pubmed]
  11. Tissue expression of neu differentiation factor/heregulin and its receptor complex in prostate cancer and its biologic effects on prostate cancer cells in vitro. Lyne, J.C., Melhem, M.F., Finley, G.G., Wen, D., Liu, N., Deng, D.H., Salup, R. The cancer journal from Scientific American. (1997) [Pubmed]
  12. Expression of c-erbB-4/HER4 is regulated in T47D breast carcinoma cells by retinoids and vitamin D3. Offterdinger, M., Schneider, S.M., Huber, H., Grunt, T.W. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  13. Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities. Vidal, G.A., Naresh, A., Marrero, L., Jones, F.E. J. Biol. Chem. (2005) [Pubmed]
  14. Regulation of mouse mammary gland development and tumorigenesis by the ERBB signaling network. Troyer, K.L., Lee, D.C. Journal of mammary gland biology and neoplasia. (2001) [Pubmed]
  15. Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation. Elenius, K., Paul, S., Allison, G., Sun, J., Klagsbrun, M. EMBO J. (1997) [Pubmed]
  16. Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5. Long, W., Wagner, K.U., Lloyd, K.C., Binart, N., Shillingford, J.M., Hennighausen, L., Jones, F.E. Development (2003) [Pubmed]
  17. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Plowman, G.D., Culouscou, J.M., Whitney, G.S., Green, J.M., Carlton, G.W., Foy, L., Neubauer, M.G., Shoyab, M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  18. Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. Xia, W., Lau, Y.K., Zhang, H.Z., Xiao, F.Y., Johnston, D.A., Liu, A.R., Li, L., Katz, R.L., Hung, M.C. Clin. Cancer Res. (1999) [Pubmed]
  19. Type 1 receptor tyrosine kinases are differentially phosphorylated in mammary carcinoma and differentially associated with steroid receptors. Bacus, S.S., Chin, D., Yarden, Y., Zelnick, C.R., Stern, D.F. Am. J. Pathol. (1996) [Pubmed]
  20. Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer? Tovey, S., Dunne, B., Witton, C.J., Forsyth, A., Cooke, T.G., Bartlett, J.M. Clin. Cancer Res. (2005) [Pubmed]
  21. Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype. Leach, R.E., Kilburn, B., Wang, J., Liu, Z., Romero, R., Armant, D.R. Dev. Biol. (2004) [Pubmed]
  22. The HER4 cytoplasmic domain, but not its C terminus, inhibits mammary cell proliferation. Feng, S.M., Sartor, C.I., Hunter, D., Zhou, H., Yang, X., Caskey, L.S., Dy, R., Muraoka-Cook, R.S., Earp, H.S. Mol. Endocrinol. (2007) [Pubmed]
  23. Expression of the erbB-2 family of growth factor receptors and their ligands in breast cancers. Implication for tumor biology and clinical behavior. Bacus, S.S., Zelnick, C.R., Plowman, G., Yarden, Y. Am. J. Clin. Pathol. (1994) [Pubmed]
  24. HB-EGF is produced in the peritoneal cavity and enhances mesothelial cell adhesion and migration. Faull, R.J., Stanley, J.M., Fraser, S., Power, D.A., Leavesley, D.I. Kidney Int. (2001) [Pubmed]
  25. 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]
  26. Gene expression and immunolocalization of heparin-binding epidermal growth factor-like growth factor and human epidermal growth factor receptors in human corpus luteum. Akayama, Y., Takekida, S., Ohara, N., Tateiwa, H., Chen, W., Nakabayashi, K., Maruo, T. Hum. Reprod. (2005) [Pubmed]
  27. Prognostic value of ERBB family mRNA expression in breast carcinomas. Bièche, I., Onody, P., Tozlu, S., Driouch, K., Vidaud, M., Lidereau, R. Int. J. Cancer (2003) [Pubmed]
  28. Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Memon, A.A., Sorensen, B.S., Melgard, P., Fokdal, L., Thykjaer, T., Nexo, E. Br. J. Cancer (2004) [Pubmed]
  29. Ligand-directed retroviral targeting of human breast cancer cells. Han, X., Kasahara, N., Kan, Y.W. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  30. Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Gilbertson, R.J., Perry, R.H., Kelly, P.J., Pearson, A.D., Lunec, J. Cancer Res. (1997) [Pubmed]
  31. Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Barnes, N.L., Khavari, S., Boland, G.P., Cramer, A., Knox, W.F., Bundred, N.J. Clin. Cancer Res. (2005) [Pubmed]
  32. Expression of EGFR, HER2, HER3, and HER4 in metastatic squamous cell carcinomas of the oral cavity and base of tongue. Ekberg, T., Nestor, M., Engström, M., Nordgren, H., Wester, K., Carlsson, J., Anniko, M. Int. J. Oncol. (2005) [Pubmed]
  33. Novel ERBB4 juxtamembrane splice variants are frequently expressed in childhood medulloblastoma. Gilbertson, R., Hernan, R., Pietsch, T., Pinto, L., Scotting, P., Allibone, R., Ellison, D., Perry, R., Pearson, A., Lunec, J. Genes Chromosomes Cancer (2001) [Pubmed]
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