Skip to main content

Advertisement

SpringerLink
Log in

The biology of human epidermal growth factor receptor 2

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Our understanding of the normal signaling mechanisms and functions of human epidermal growth factor receptor 2 (HER2) and other members of the HER family, namely epidermal growth factor receptor, HER3, and HER4, is growing rapidly. Activation of these receptors results in a diverse array of signals through the formation of homodimeric and heterodimeric receptor complexes; HER2 is the preferred dimerization partner for the other HERs. These oligomeric receptor complexes activate distinct signaling pathways, such as the Ras-MAPK and PI3-kinase pathways. These, in turn, affect various cellular processes. Recent gene deletion experiments in mice point to an important role for HER2 in cardiac and neural development, and evidence from other studies indicates that HER2 is involved in normal breast growth and development. Thus, HER2 is a key component of a complex signaling network that plays a critical role in the regulation of tissue development, growth, and differentiation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Earp HS, Dawson TL, 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, 35:115–132.

    Article  PubMed  CAS  Google Scholar 

  2. Pinkas-Kramarski R, Lenferink AEG, Bacus SS, et al.: The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin. Oncogene 1998, 16:1249–1258.

    Article  PubMed  CAS  Google Scholar 

  3. Chang H, Riese DJI, Gilbert W, et al.: Ligands for ErbB-family receptors encoded by a neuregulin-like gene. Nature 1997, 387:509–512.

    Article  PubMed  CAS  Google Scholar 

  4. Burden S, Yarden Y: Neuregulins and their receptors: a versatile signaling module in organogenesis and oncogenesis. Neuron 1997, 18:847–855.

    Article  PubMed  CAS  Google Scholar 

  5. Revillion F, Bonneterre J, Peyrat JP: ErbB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer 1998, 34:791–808.

    Article  PubMed  CAS  Google Scholar 

  6. Pinkas-Kramarski P, Soussan L, Waterman H, et al.: Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J 1996, 15:2452–2467.

    PubMed  CAS  Google Scholar 

  7. Zhang K, Sun JL, Liu NL, et al.: Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2. J Biol Chem 1996, 271:3884–3890.

    Article  PubMed  CAS  Google Scholar 

  8. Graus-Porta D, Beerli RR, Daly JM, et al.: ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 1997, 16:1647–1655. This paper examines the role of ErbB2 as a critical component and heterodimerization partner important for signaling by all ErbB family members. It provides the first biochemical evidence that acquisition of distinct signaling properties depends on the ErbB dimerization partner.

    Article  PubMed  CAS  Google Scholar 

  9. Sierke SL, Cheng KR, Kim HH, Koland JG: Biochemical characterization of the protein tyrosine kinase homology domain of the ErbB3 (Her3) receptor protein. Biochem J 1997 322(part 3):757–763.

    PubMed  CAS  Google Scholar 

  10. Kim HH, Vijapurkar U, Hellyer NJ, et al.: Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein. Biochem J 1998, 334(part 1):189–195.

    PubMed  CAS  Google Scholar 

  11. Schaefer G, Akita RW, Sliwkowski MX: A discrete three-amino acid segment (LVI) at the C-terminal end of kinase-impaired ErbB3 is required for transactivation of ErbB2. J Biol Chem 1999, 274:859–866.

    Article  PubMed  CAS  Google Scholar 

  12. Sliwkowski MX, Schaefer G, Akita RW, et al.: Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 1994, 269:14661–14665.

    PubMed  CAS  Google Scholar 

  13. Pinkas-Kramarski R, Alroy I, Yarden Y: ErbB receptors and EGF-like ligands: cell lineage determination and oncogenesis through combinatorial signaling. J Mammary Gland Biol Neoplasia 1997, 2:97–107.

    Article  PubMed  CAS  Google Scholar 

  14. Tzahar E, Yarden Y: The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphanhood to multiple stromal ligands. Biochim Biophys Acta 1998, 1377:M25-M37.

    PubMed  CAS  Google Scholar 

  15. Kokai Y, Myers JN, Wada T, et al.: Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts. Cell 1989, 58:287–292.

    Article  PubMed  CAS  Google Scholar 

  16. Alimandi M, Romano A, Curia MC, et al.: Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 1995, 10:1813–1821.

    PubMed  CAS  Google Scholar 

  17. Wallasch C, Weiss FU, Niederfellner G, et al.: Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J 1995, 14:4267–4275.

    PubMed  CAS  Google Scholar 

  18. Soltoff SP, Carraway KL 3d, Prigent SA, Gullick WG, Cantley LC:ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol 1994, 14:3550–3558.

    PubMed  CAS  Google Scholar 

  19. Carraway KL 3d, Soltoff SP, Diamonti AJ, Cantley LC:Heregulin stimulates mitogenesis and phosphatidylinositol 3-kinase in mouse fibroblasts transfected with erbB2/neu and erbB3. J Biol Chem 1995, 270:7111–7116.

    Article  PubMed  CAS  Google Scholar 

  20. Wada T, Qian XL, Greene MI: Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell 1990, 61:1339–1347.

    Article  PubMed  CAS  Google Scholar 

  21. Murali R, Brennan PJ, Kieberemmons T, Greene MI: Structural analysis of p185(C-Neu) and epidermal growth factor receptor tyrosine kinases—oligomerization of kinase domains. Proc Natl Acad Sci U S A 1996, 93:6252–6257.

    Article  PubMed  CAS  Google Scholar 

  22. Wilde A, Beattie EC, Lem L, et al.: EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake. Cell 1999, 96:677–687.

    Article  PubMed  CAS  Google Scholar 

  23. Waterman H, Sabanai I, Geiger B, Yarden Y: Alternative intracellular routing of ErbB receptors may determine signaling potency. J Biol Chem 1998, 273:13819–13827.

    Article  PubMed  CAS  Google Scholar 

  24. Worthylake R, Opresko LK, Wiley HS: ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem 1999, 274:8865–8874. This paper demonstrates a distinctive mode of ErbB receptor regulation whereby heterodimerization with ErbB2 can alter epidermal growth factor receptor activation. Similar mechanisms may also be important for regulation of other ErbB family members.

    Article  PubMed  CAS  Google Scholar 

  25. Lenferink AEG, Pinkaskramarski R, Vandepoll MLM, et al.:Differential endocytic routing of homo-and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J 1998, 17:3385–3397.

    Article  PubMed  CAS  Google Scholar 

  26. Tari AM, Hung MC, Li KY, Lopez-Berestein G: Growth inhibition of breast cancer cells by Grb2 downregulation is correlated with inactivation of mitogen-activated protein kinase in EGFR, but not in ErbB2, cells. Oncogene 1999, 18:1325–1332.

    Article  PubMed  CAS  Google Scholar 

  27. Wright JD, Reuter CW, Weber MJ: An incomplete program of cellular tyrosine phosphorylations induced by kinasedefective epidermal growth factor receptors. J Biol Chem 1995, 270:12085–12093.

    Article  PubMed  CAS  Google Scholar 

  28. Hazan R, Margolis B, Dombalagian M, et al.: Identification of autophosphorylation sites of HER2/neu. Cell Growth Differ 1990, 1:3–7.

    PubMed  CAS  Google Scholar 

  29. Dankort DL, Wang ZX, Blackmore V, et al.: Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation. Mol Cell Biol 1997, 17:5410–5425.

    PubMed  CAS  Google Scholar 

  30. Vijapurkar U, Cheng KR, Koland JG: Mutation of a shc binding site tyrosine residue in ErbB3/HER3 blocks heregulindependent activation of mitogen-activated protein kinase. J Biol Chem 1998, 273:20996–21002.

    Article  PubMed  CAS  Google Scholar 

  31. Lange CA, Richer JK, Shen TJ, Horwitz KB: Convergence of progesterone and epidermal growth factor signaling in breast cancer—potentiation of mitogen-activated protein kinase pathways. J Biol Chem 1998, 273:31308–31316.

    Article  PubMed  CAS  Google Scholar 

  32. Levkowitz G, Klapper LN, Tzahar E, et al.: Coupling of the C-Cbl protooncogene product to ErbB-1/EGF-receptor but not to other ErbB proteins. Oncogene 1996, 12:1117–1125.

    PubMed  CAS  Google Scholar 

  33. Tan M, Grijalva R, Yu DH: Heregulin beta 1-activated phosphatidylinositol 3-kinase enhances aggregation of MCF-7 breast cancer cells independent of extracellular signal-regulated kinase. Cancer Res 1999, 59:1620–1625.

    PubMed  CAS  Google Scholar 

  34. Adam L, Vadlamudi R, Kondapaka SB, et al.: Heregulin regulates cytoskeletal reorganization and cell migration through the P21-activated kinase-1 via phosphatidylinositol-3 kinase. J Biol Chem 1998, 273:28238–28246.

    Article  PubMed  CAS  Google Scholar 

  35. Bos JL: A target for phosphoinositide 3-kinase: Akt/PKB. Trends Biochem Sci 1995, 20:441–442.

    Article  PubMed  CAS  Google Scholar 

  36. Olayioye MA, Grausporta D, Beerli RR, et al.: ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol 1998, 18:5042–5051.

    PubMed  CAS  Google Scholar 

  37. Karunagaran D, Tzahar E, Beerli RR, et al.: ErbB-2 is a common auxiliary subunit of NDF and EGF receptors—implications for breast cancer. EMBO J 1996, 15:254–264.

    PubMed  CAS  Google Scholar 

  38. Krymskaya VP, Hoffman R, Eszterhas A, et al.: EGF activates ErbB-2 and stimulates phosphatidylinositol 3-kinase in human airway smooth muscle cells. Am J Physiol 1999, 20:L246-L55.

    Google Scholar 

  39. Schroeder JA, Lee DC: Dynamic expression and activation of ErbB receptors in the developing mouse mammary gland. Cell Growth Differ 1998, 9:451–464. This paper provides an extensive analysis of the mammary expression pattern of different human epidermal growth factor receptors. It strongly indicates the involvement of these receptors in normal breast growth and development.

    PubMed  CAS  Google Scholar 

  40. Gompel A, Martin A, Simon P, et al.: Epidermal growth factor receptor and c-erbB-2 expression in normal breast tissue during the menstrual cycle. Breast Cancer Res Treat 1996, 38:227–235.

    Article  PubMed  CAS  Google Scholar 

  41. Meyer D, Birchmeyer C: Multiple essential functions of neuregulin in development. Nature 1995, 378:386–390.

    Article  PubMed  CAS  Google Scholar 

  42. Lee K-F, Simon H, Chen H, et al.: Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995, 378:394–398.

    Article  PubMed  CAS  Google Scholar 

  43. Gassmann M, Casagranda F, Orioli D, et al.: Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 1995, 378:390–394.

    Article  PubMed  CAS  Google Scholar 

  44. Erickson SL, O’Shea KS, Ghaboosi N, et al.: ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice. Development 1997, 124:4999–5011. This paper concisely summarizes the cardiac and neural defects seen in ErbB2-, ErbB3-, and heregulin-deficient mice.

    PubMed  CAS  Google Scholar 

  45. Zhao Y, Sawyer DR, Baliga RR, et al.: Neuregulins promote the survival and growth of cardiac myocytes. J Biol Chem 1998, 273:10261–10269. Data from in vitro studies further strengthen the evidence of the involvement of ErbB receptors and neuregulins in cardiac myocyte growth and survival.

    Article  PubMed  CAS  Google Scholar 

  46. Grinspan JB, Marchionni MA, Reeves M, et al.: Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins. J Neurosci 1996, 16:6107–6118.

    PubMed  CAS  Google Scholar 

  47. Levi ADO, Bunge RP, Lofgren JA, et al.: The influence of heregulins on human Schwann cell proliferation. J Neurosci 1995, 15:1329–1340.

    PubMed  CAS  Google Scholar 

  48. Schechter AL, Stern DF, Vaidyanathan L, et al.: The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 1984, 312:513–516.

    Article  PubMed  CAS  Google Scholar 

  49. Padhy LC, Shih C, Cowing D, et al.: Identification of a phosphoprotein specifically induced by the transforming DNA of rat neuroblastomas. Cell 1982, 28:865–871.

    Article  PubMed  CAS  Google Scholar 

  50. Perantoni AO, Rice JM, Reed CD, et al.: Activated neu oncogene sequences in primary tumors of peripheral nervous system induced in rats by transplacental exposure to ethylnitrosourea. Proc Natl Acad Sci U S A 1987, 84:6317–6321.

    Article  PubMed  CAS  Google Scholar 

  51. Nikitin AY, Jin JJ, Papewalis J, et al.: Wild type neu oncogene counteracts mutant homologue in malignant transformation of rat Schwann cells. Oncogene 1996, 12:1309–1317.

    PubMed  CAS  Google Scholar 

  52. Cohen JA, Yachnis AT, Arai M, et al.: Expression of the neu proto-oncogene by Schwann cells during peripheral nerve development and Wallerian degeneration. J Neurosci Res 1992, 31:622–634.

    Article  PubMed  CAS  Google Scholar 

  53. Carroll SL, Miller ML, Frohnert PW, et al.: Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J Neurosci 1997, 17:1642–1659.

    PubMed  CAS  Google Scholar 

  54. Falls DL, Rosen KM, Corfas G, et al.: ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 1993, 72:801–815.

    Article  PubMed  CAS  Google Scholar 

  55. Moscoco LM, Chu GC, Gautam M, et al.: Synapse-associated expression of an acetylcholine receptor-inducing protein, ARIA/Heregulin, and its putative receptors, ErbB2 and ErbB3, in developing mammalian muscle. Dev Biol 1995, 172:158–169.

    Article  Google Scholar 

  56. Carraway KL 3d, Weber JL, Unger MJ, et al.: Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 1997, 387:512–516.

    Article  PubMed  CAS  Google Scholar 

  57. Zhang D, Sliwkowski MX, Mark M, et al.: Neuregulin-3: a novel neural tissue-specific protein which binds and activates ErbB4. Proc Natl Acad Sci U S A 1997, 94:9562–9567.

    Article  PubMed  CAS  Google Scholar 

  58. Harari D, Tzahar E, Romano J, et al.: Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene 1999, 18:2681–2689.

    Article  PubMed  CAS  Google Scholar 

  59. Eisenberg LM, Markwald RR: Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circ Res 1995, 77:1–6.

    PubMed  CAS  Google Scholar 

  60. Lemke G: Neuregulins in development. Mol Cell Neurosci 1996, 7:247–262.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Oncology, Genentech, Inc., MS 63, 1 DNA Way, 94080, South San Francisco, CA, USA

    Mark X. Sliwkowski PhD

Authors
  1. Srividya Sundaresan PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elicia Penuel PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark X. Sliwkowski PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sundaresan, S., Penuel, E. & Sliwkowski, M.X. The biology of human epidermal growth factor receptor 2. Curr Oncol Rep 1, 16–22 (1999). https://doi.org/10.1007/s11912-999-0005-7

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-999-0005-7

Keywords

Search

Navigation