Skip to main content
NCBI home page
Transactions of the American Clinical and Climatological Association logoLink to Transactions of the American Clinical and Climatological Association
. 2003;114:315–334.

The EGF receptor family--multiple roles in proliferation, differentiation, and neoplasia with an emphasis on HER4.

H Shelton Earp 3rd 1, Benjamin F Calvo 1, Carolyn I Sartor 1
PMCID: PMC2194503  PMID: 12813928

Abstract

The EGF Receptor (EGFR), the first transmembrane receptor tyrosine kinase cloned and sequenced, and its closely related family members HER2, HER3, and HER4, play myriad roles in mammalian growth and development. Receptor activation involves ligand binding to separate receptors followed by formation of active dimers. These receptors can signal as homodimers or they can subtly alter signaling output by heterodimerizing with other family members. Adding complexity, these receptors with varying specificity bind at least 10 ligands from two ligand families, the EGF and neuregulin/heregulin families. This signaling system's impact on human neoplasia is underscored by the following: i.) EGFR is overexpressed or activated by autocrine or paracrine growth factor loops in at least 50% of epithelial malignancies; ii.) HER2 is amplified and dramatically overexpressed in approximately 20%-25% or breast cancers; iii) HER3 and HER4 are variably expressed in breast and other cancers. Overexpression and/or activation of EGFR, HER2 and HER3 has been correlated with poor tumor prognosis; antibody and small molecule inhibitors of their activity are being tested as therapy in cancer patients. However, the signaling complexity engendered by four interacting receptors and ten ligands makes it difficult to definitively measure receptor signaling output in human tumors and even makes mechanistic studies of the family's role in normal physiology and neoplastic transformation a challenge. In spite of the literature's emphasis on growth control, activation by some EGF receptor family member ligands can produce tumor cell differentiation, characterized by growth cessation and differentiation gene product synthesis. The present work delineates a role for HER4 in breast cancer cell differentiation and demonstrates that HER4 is both necessary and sufficient to produce an anti-proliferative signal. These

Full text

PDF
315

Images in this article

317Fig. 1
on p.317
318Fig. 2
on p.318
320Fig. 3
on p.320
321Fig. 4
on p.321
324Fig. 5
on p.324
325Fig. 6
on p.325
326Fig. 7
on p.326

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aroian R. V., Koga M., Mendel J. E., Ohshima Y., Sternberg P. W. The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily. Nature. 1990 Dec 20;348(6303):693–699. doi: 10.1038/348693a0. [DOI] [PubMed] [Google Scholar]
  2. Bacus S. S., Gudkov A. V., Zelnick C. R., Chin D., Stern R., Stancovski I., Peles E., Ben-Baruch N., Farbstein H., Lupu R. Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors. Cancer Res. 1993 Nov 1;53(21):5251–5261. [PubMed] [Google Scholar]
  3. Baker N. E., Yu S. Y. The EGF receptor defines domains of cell cycle progression and survival to regulate cell number in the developing Drosophila eye. Cell. 2001 Mar 9;104(5):699–708. doi: 10.1016/s0092-8674(01)00266-5. [DOI] [PubMed] [Google Scholar]
  4. Bargmann C. I., Hung M. C., Weinberg R. A. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986 Jan 16;319(6050):226–230. doi: 10.1038/319226a0. [DOI] [PubMed] [Google Scholar]
  5. Beerli R. R., Hynes N. E. Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. J Biol Chem. 1996 Mar 15;271(11):6071–6076. doi: 10.1074/jbc.271.11.6071. [DOI] [PubMed] [Google Scholar]
  6. COHEN S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem. 1962 May;237:1555–1562. [PubMed] [Google Scholar]
  7. Cobleigh M. A., Vogel C. L., Tripathy D., Robert N. J., Scholl S., Fehrenbacher L., Wolter J. M., Paton V., Shak S., Lieberman G. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999 Sep;17(9):2639–2648. doi: 10.1200/JCO.1999.17.9.2639. [DOI] [PubMed] [Google Scholar]
  8. Culouscou J. M., Plowman G. D., Carlton G. W., Green J. M., Shoyab M. Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor. J Biol Chem. 1993 Sep 5;268(25):18407–18410. [PubMed] [Google Scholar]
  9. Daly J. M., Jannot C. B., Beerli R. R., Graus-Porta D., Maurer F. G., Hynes N. E. Neu differentiation factor induces ErbB2 down-regulation and apoptosis of ErbB2-overexpressing breast tumor cells. Cancer Res. 1997 Sep 1;57(17):3804–3811. [PubMed] [Google Scholar]
  10. Di Fiore P. P., Pierce J. H., Kraus M. H., Segatto O., King C. R., Aaronson S. A. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science. 1987 Jul 10;237(4811):178–182. doi: 10.1126/science.2885917. [DOI] [PubMed] [Google Scholar]
  11. Di Fiore P. P., Segatto O., Taylor W. G., Aaronson S. A., Pierce J. H. EGF receptor and erbB-2 tyrosine kinase domains confer cell specificity for mitogenic signaling. Science. 1990 Apr 6;248(4951):79–83. doi: 10.1126/science.2181668. [DOI] [PubMed] [Google Scholar]
  12. Domínguez M., Wasserman J. D., Freeman M. Multiple functions of the EGF receptor in Drosophila eye development. Curr Biol. 1998 Sep 24;8(19):1039–1048. doi: 10.1016/s0960-9822(98)70441-5. [DOI] [PubMed] [Google Scholar]
  13. Downward J., Yarden Y., Mayes E., Scrace G., Totty N., Stockwell P., Ullrich A., Schlessinger J., Waterfield M. D. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature. 1984 Feb 9;307(5951):521–527. doi: 10.1038/307521a0. [DOI] [PubMed] [Google Scholar]
  14. Druker Brian J. Inhibition of the Bcr-Abl tyrosine kinase as a therapeutic strategy for CML. Oncogene. 2002 Dec 9;21(56):8541–8546. doi: 10.1038/sj.onc.1206081. [DOI] [PubMed] [Google Scholar]
  15. Earp H. S., Dawson T. L., Li X., Yu H. Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research. Breast Cancer Res Treat. 1995 Jul;35(1):115–132. doi: 10.1007/BF00694752. [DOI] [PubMed] [Google Scholar]
  16. Fox S. B., Smith K., Hollyer J., Greenall M., Hastrich D., Harris A. L. The epidermal growth factor receptor as a prognostic marker: results of 370 patients and review of 3009 patients. Breast Cancer Res Treat. 1994 Jan;29(1):41–49. doi: 10.1007/BF00666180. [DOI] [PubMed] [Google Scholar]
  17. Garrett Thomas P. J., McKern Neil M., Lou Meizhen, Elleman Thomas C., Adams Timothy E., Lovrecz George O., Zhu Hong-Jian, Walker Francesca, Frenkel Morry J., Hoyne Peter A. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha. Cell. 2002 Sep 20;110(6):763–773. doi: 10.1016/s0092-8674(02)00940-6. [DOI] [PubMed] [Google Scholar]
  18. Gassmann M., Casagranda F., Orioli D., Simon H., Lai C., Klein R., Lemke G. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature. 1995 Nov 23;378(6555):390–394. doi: 10.1038/378390a0. [DOI] [PubMed] [Google Scholar]
  19. Guttridge Katherine L., Luft J. Christopher, Dawson Thomas L., Kozlowska Eva, Mahajan Nupam P., Varnum Brian, Earp H. Shelton. Mer receptor tyrosine kinase signaling: prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation. J Biol Chem. 2002 Apr 2;277(27):24057–24066. doi: 10.1074/jbc.M112086200. [DOI] [PubMed] [Google Scholar]
  20. Hawkins R. A., Tesdale A. L., Killen M. E., Jack W. J., Chetty U., Dixon J. M., Hulme M. J., Prescott R. J., McIntyre M. A., Miller W. R. Prospective evaluation of prognostic factors in operable breast cancer. Br J Cancer. 1996 Nov;74(9):1469–1478. doi: 10.1038/bjc.1996.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Holmes W. E., Sliwkowski M. X., Akita R. W., Henzel W. J., Lee J., Park J. W., Yansura D., Abadi N., Raab H., Lewis G. D. Identification of heregulin, a specific activator of p185erbB2. Science. 1992 May 22;256(5060):1205–1210. doi: 10.1126/science.256.5060.1205. [DOI] [PubMed] [Google Scholar]
  22. Hunter T., Cooper J. A. Protein-tyrosine kinases. Annu Rev Biochem. 1985;54:897–930. doi: 10.1146/annurev.bi.54.070185.004341. [DOI] [PubMed] [Google Scholar]
  23. Hunter T. Signaling--2000 and beyond. Cell. 2000 Jan 7;100(1):113–127. doi: 10.1016/s0092-8674(00)81688-8. [DOI] [PubMed] [Google Scholar]
  24. Kapitanović S., Radosević S., Slade N., Kapitanović M., Andelinović S., Ferencić Z., Tavassoli M., Spaventi S., Pavelić K., Spaventi R. Expression of erbB-3 protein in colorectal adenocarcinoma: correlation with poor survival. J Cancer Res Clin Oncol. 2000 Apr;126(4):205–211. doi: 10.1007/s004320050034. [DOI] [PubMed] [Google Scholar]
  25. Kataoka H., Joh T., Kasugai K., Okayama N., Moriyama A., Asai K., Kato T. Expression of mRNA for heregulin and its receptor, ErbB-3 and ErbB-4, in human upper gastrointestinal mucosa. Life Sci. 1998;63(7):553–564. doi: 10.1016/s0024-3205(98)00306-3. [DOI] [PubMed] [Google Scholar]
  26. Koenders P. G., Beex L. V., Kienhuis C. B., Kloppenborg P. W., Benraad T. J. Epidermal growth factor receptor and prognosis in human breast cancer: a prospective study. Breast Cancer Res Treat. 1993;25(1):21–27. doi: 10.1007/BF00662397. [DOI] [PubMed] [Google Scholar]
  27. Kramer R., Bucay N., Kane D. J., Martin L. E., Tarpley J. E., Theill L. E. Neuregulins with an Ig-like domain are essential for mouse myocardial and neuronal development. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4833–4838. doi: 10.1073/pnas.93.10.4833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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 Natl Acad Sci U S A. 1989 Dec;86(23):9193–9197. doi: 10.1073/pnas.86.23.9193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lee Hahn-Jun, Jung Kwang-Mook, Huang Yang Z., Bennett Lori B., Lee Joanne S., Mei Lin, Kim Tae-Wan. Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J Biol Chem. 2001 Dec 10;277(8):6318–6323. doi: 10.1074/jbc.M110371200. [DOI] [PubMed] [Google Scholar]
  30. Lee J., Dull T. J., Lax I., Schlessinger J., Ullrich A. HER2 cytoplasmic domain generates normal mitogenic and transforming signals in a chimeric receptor. EMBO J. 1989 Jan;8(1):167–173. doi: 10.1002/j.1460-2075.1989.tb03361.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lee K. F., Simon H., Chen H., Bates B., Hung M. C., Hauser C. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature. 1995 Nov 23;378(6555):394–398. doi: 10.1038/378394a0. [DOI] [PubMed] [Google Scholar]
  32. Lehväslaiho H., Lehtola L., Sistonen L., Alitalo K. A chimeric EGF-R-neu proto-oncogene allows EGF to regulate neu tyrosine kinase and cell transformation. EMBO J. 1989 Jan;8(1):159–166. doi: 10.1002/j.1460-2075.1989.tb03360.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lesa G. M., Sternberg P. W. Positive and negative tissue-specific signaling by a nematode epidermal growth factor receptor. Mol Biol Cell. 1997 May;8(5):779–793. doi: 10.1091/mbc.8.5.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Mendelsohn J. The epidermal growth factor receptor as a target for cancer therapy. Endocr Relat Cancer. 2001 Mar;8(1):3–9. doi: 10.1677/erc.0.0080003. [DOI] [PubMed] [Google Scholar]
  35. Meyer D., Birchmeier C. Multiple essential functions of neuregulin in development. Nature. 1995 Nov 23;378(6555):386–390. doi: 10.1038/378386a0. [DOI] [PubMed] [Google Scholar]
  36. Murray P. A., Barrett-Lee P., Travers M., Luqmani Y., Powles T., Coombes R. C. The prognostic significance of transforming growth factors in human breast cancer. Br J Cancer. 1993 Jun;67(6):1408–1412. doi: 10.1038/bjc.1993.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Naidu R., Yadav M., Nair S., Kutty M. K. Expression of c-erbB3 protein in primary breast carcinomas. Br J Cancer. 1998 Nov;78(10):1385–1390. doi: 10.1038/bjc.1998.689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ni C. Y., Murphy M. P., Golde T. E., Carpenter G. gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science. 2001 Oct 25;294(5549):2179–2181. doi: 10.1126/science.1065412. [DOI] [PubMed] [Google Scholar]
  39. Ogiso Hideo, Ishitani Ryuichiro, Nureki Osamu, Fukai Shuya, Yamanaka Mari, Kim Jae-Hoon, Saito Kazuki, Sakamoto Ayako, Inoue Mio, Shirouzu Mikako. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell. 2002 Sep 20;110(6):775–787. doi: 10.1016/s0092-8674(02)00963-7. [DOI] [PubMed] [Google Scholar]
  40. Olayioye M. A., Neve R. M., Lane H. A., Hynes N. E. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000 Jul 3;19(13):3159–3167. doi: 10.1093/emboj/19.13.3159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Paik S., Hazan R., Fisher E. R., Sass R. E., Fisher B., Redmond C., Schlessinger J., Lippman M. E., King C. R. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol. 1990 Jan;8(1):103–112. doi: 10.1200/JCO.1990.8.1.103. [DOI] [PubMed] [Google Scholar]
  42. Peles E., Bacus S. S., Koski R. A., Lu H. S., Wen D., Ogden S. G., Levy R. B., Yarden Y. Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell. 1992 Apr 3;69(1):205–216. doi: 10.1016/0092-8674(92)90131-u. [DOI] [PubMed] [Google Scholar]
  43. Peles E., Yarden Y. Neu and its ligands: from an oncogene to neural factors. Bioessays. 1993 Dec;15(12):815–824. doi: 10.1002/bies.950151207. [DOI] [PubMed] [Google Scholar]
  44. Plowman G. D., Culouscou J. M., Whitney G. S., Green J. M., Carlton G. W., Foy L., Neubauer M. G., Shoyab M. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746–1750. doi: 10.1073/pnas.90.5.1746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Riese D. J., 2nd, Stern D. F. Specificity within the EGF family/ErbB receptor family signaling network. Bioessays. 1998 Jan;20(1):41–48. doi: 10.1002/(SICI)1521-1878(199801)20:1<41::AID-BIES7>3.0.CO;2-V. [DOI] [PubMed] [Google Scholar]
  46. Riese D. J., 2nd, van Raaij T. M., Plowman G. D., Andrews G. C., Stern D. F. The cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol Cell Biol. 1995 Oct;15(10):5770–5776. doi: 10.1128/mcb.15.10.5770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Santoro M., Wong W. T., Aroca P., Santos E., Matoskova B., Grieco M., Fusco A., di Fiore P. P. An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway. Mol Cell Biol. 1994 Jan;14(1):663–675. doi: 10.1128/mcb.14.1.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Sartor C. I., Zhou H., Kozlowska E., Guttridge K., Kawata E., Caskey L., Harrelson J., Hynes N., Ethier S., Calvo B. Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol. 2001 Jul;21(13):4265–4275. doi: 10.1128/MCB.21.13.4265-4275.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Schechter A. L., Hung M. C., Vaidyanathan L., Weinberg R. A., Yang-Feng T. L., Francke U., Ullrich A., Coussens L. The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science. 1985 Sep 6;229(4717):976–978. doi: 10.1126/science.2992090. [DOI] [PubMed] [Google Scholar]
  50. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000 Oct 13;103(2):211–225. doi: 10.1016/s0092-8674(00)00114-8. [DOI] [PubMed] [Google Scholar]
  51. Schlessinger Joseph. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002 Sep 20;110(6):669–672. doi: 10.1016/s0092-8674(02)00966-2. [DOI] [PubMed] [Google Scholar]
  52. Slamon D. J., Clark G. M., Wong S. G., Levin W. J., Ullrich A., McGuire W. L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987 Jan 9;235(4785):177–182. doi: 10.1126/science.3798106. [DOI] [PubMed] [Google Scholar]
  53. Srinivasan R., Gillett C. E., Barnes D. M., Gullick W. J. Nuclear expression of the c-erbB-4/HER-4 growth factor receptor in invasive breast cancers. Cancer Res. 2000 Mar 15;60(6):1483–1487. [PubMed] [Google Scholar]
  54. Srinivasan R., Poulsom R., Hurst H. C., Gullick W. J. Expression of the c-erbB-4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types. J Pathol. 1998 Jul;185(3):236–245. doi: 10.1002/(SICI)1096-9896(199807)185:3<236::AID-PATH118>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  55. Suo Z., Berner H. S., Risberg B., Karlsson M. G., Nesland J. M. Estrogen receptor-alpha and C-ERBB-4 expression in breast carcinomas. Virchows Arch. 2001 Jul;439(1):62–69. doi: 10.1007/s004280000392. [DOI] [PubMed] [Google Scholar]
  56. Suo Zhenhe, Risberg Bjørn, Kalsson Mats G., Willman Kenneth, Tierens Anne, Skovlund Eva, Nesland Jahn M. EGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival. J Pathol. 2002 Jan;196(1):17–25. doi: 10.1002/path.1003. [DOI] [PubMed] [Google Scholar]
  57. Sweeney C., Lai C., Riese D. J., 2nd, Diamonti A. J., Cantley L. C., Carraway K. L., 3rd Ligand discrimination in signaling through an ErbB4 receptor homodimer. J Biol Chem. 2000 Jun 30;275(26):19803–19807. doi: 10.1074/jbc.C901015199. [DOI] [PubMed] [Google Scholar]
  58. Tzahar E., Waterman H., Chen X., Levkowitz G., Karunagaran D., Lavi S., Ratzkin B. J., Yarden Y. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 1996 Oct;16(10):5276–5287. doi: 10.1128/mcb.16.10.5276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Ullrich A., Coussens L., Hayflick J. S., Dull T. J., Gray A., Tam A. W., Lee J., Yarden Y., Libermann T. A., Schlessinger J. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. 1984 May 31-Jun 6Nature. 309(5967):418–425. doi: 10.1038/309418a0. [DOI] [PubMed] [Google Scholar]

Articles from Transactions of the American Clinical and Climatological Association are provided here courtesy of American Clinical and Climatological Association

RESOURCES