Skip to main content

ErbB Receptor Negative Regulatory Mechanisms: Implications in Cancer

Journal of Mammary Gland Biology and Neoplasia volume 11, pages 89–99 (2006)Cite this article

Abstract

Activation of ErbB receptor tyrosine kinases (RTKs) must be precisely regulated to ensure the fidelity of developmental and homeostatic processes mediated by growth factors. Insufficient receptor stimulation will lead to defects in tissue development, while excessive stimulation can lead to hyperplastic events associated with cancer and other diseases. A coordinated balance of the intensity and timing of receptor signaling, achieved through both receptor activation and negative regulatory mechanisms, is required for signaling fidelity. While considerable effort has gone into understanding mechanisms by which ErbB receptors are activated, our understanding of the suppression of growth factor receptor activity remains limited. While ligand-stimulated receptor degradation is the most thoroughly examined mechanism for preventing hyper-signaling by ErbBs, recent studies indicate that several other mechanisms act directly on receptors to suppress receptor levels, or the magnitude or duration of receptor signaling. ErbB receptor overexpression or aberrant activation contributes to the progression of numerous solid tumor types. Hence, tumor cells must overcome these endogenous receptor negative regulatory mechanisms before they can exploit ErbB receptors to achieve uncontrolled growth. Here we will discuss several proteins that directly interact with ErbB receptors to suppress signaling, highlighting the potential impact of their loss on tumor progression.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Abbreviations

RTK:

receptor tyrosine kinase

EGF:

epidermal growth factor

NRG1:

neuregulin-1

MMTV:

mouse mammary tumor virus

RALT:

receptor-associated late transducer

Nrdp1:

neuregulin receptor degradation protein-1

References

  1. Guy PM, Platko JV, Cantley LC, Cerione RA, Carraway KL, III. Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci USA 1994;91(17):8132–6.

    PubMed  CAS  Google Scholar 

  2. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000;19(13):3159–67.

    PubMed  CAS  Google Scholar 

  3. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2(2):127–37.

    PubMed  CAS  Google Scholar 

  4. Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 1997;16(7):1647–55.

    PubMed  CAS  Google Scholar 

  5. Holbro T, Civenni G, Hynes NE. The ErbB receptors and their role in cancer progression. Exp Cell Res 2003;284(1):99–110.

    PubMed  CAS  Google Scholar 

  6. Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Kofler M, Jorissen RN, Nice EC, Burgess AW, Ward CW. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 2003;11(2):495–505.

    PubMed  CAS  Google Scholar 

  7. Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M, Yokoyama S. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 2002;110(6):775–87.

    PubMed  CAS  Google Scholar 

  8. Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, Lemmon MA, Sliwkowski MX, Ward CW, Yokoyama S. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003;12(3):541–52.

    PubMed  CAS  Google Scholar 

  9. Bouyain S, Longo PA, Li S, Ferguson KM, Leahy DJ. The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Proc Natl Acad Sci USA 2005;102(42):15024–9.

    PubMed  CAS  Google Scholar 

  10. Cho HS, Leahy DJ. Structure of the extracellular region of HER3 reveals an interdomain tether. Science 2002;297(5585):1330–3.

    PubMed  CAS  Google Scholar 

  11. Sibilia M, Wagner EF. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 1995;269(5221):234–8.

    PubMed  CAS  Google Scholar 

  12. Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC, et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 1995;269(5221):230–4.

    PubMed  CAS  Google Scholar 

  13. Sibilia M, Steinbach JP, Stingl L, Aguzzi A, Wagner EF. A strain-independent postnatal neurodegeneration in mice lacking the EGF receptor. EMBO J 1998;17(3):719–31.

    PubMed  CAS  Google Scholar 

  14. Kornblum HI, Hussain R, Wiesen J, Miettinen P, Zurcher SD, Chow K, Derynck R, Werb Z. Abnormal astrocyte development and neuronal death in mice lacking the epidermal growth factor receptor. J Neurosci Res 1998;53(6):697–717.

    PubMed  CAS  Google Scholar 

  15. Miettinen PJ, Huotari M, Koivisto T, Ustinov J, Palgi J, Rasilainen S, Lehtonen E, Keski-Oja J, Otonkoski T. Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors. Development 2000;127(12):2617–27.

    PubMed  CAS  Google Scholar 

  16. Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C. Requirement for neuregulin receptor ErbB2 in neural and cardiac development. Nature 1995;378(6555):394–8.

    PubMed  CAS  Google Scholar 

  17. 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;378(6555):390–4.

    PubMed  CAS  Google Scholar 

  18. Meyer D, Birchmeier C. Multiple essential functions of neuregulin in development. Nature 1995;378(6555):386–90.

    PubMed  CAS  Google Scholar 

  19. Erickson SL, O'Shea KS, Ghaboosi N, Loverro L, Frantz G, Bauer M, Lu LH, Moore MW. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2- and heregulin-deficient mice. Development 1997;124(24):4999–5011.

    PubMed  CAS  Google Scholar 

  20. Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C. Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 1997;389(6652):725–30.

    PubMed  CAS  Google Scholar 

  21. Wiesen JF, Young P, Werb Z, Cunha GR. Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. Development 1999;126(2):335–44.

    PubMed  CAS  Google Scholar 

  22. Tidcombe H, Jackson-Fisher A, Mathers K, Stern DF, Gassmann M, Golding JP. Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci USA 2003;100(14):8281–6.

    PubMed  CAS  Google Scholar 

  23. Long W, Wagner KU, Lloyd KC, Binart N, Shillingford JM, Hennighausen L, Jones FE. Impaired differentiation and lactational failure of ErbB4-deficient mammary glands identify ErbB4 as an obligate mediator of STAT5. Development 2003; 130(21):5257–68.

    PubMed  CAS  Google Scholar 

  24. Andrechek ER, White D, Muller WJ. Targeted disruption of ErbB2/Neu in the mammary epithelium results in impaired ductal outgrowth. Oncogene 2005;24(5):932–7.

    PubMed  CAS  Google Scholar 

  25. Jackson-Fisher AJ, Bellinger G, Ramabhadran R, Morris JK, Lee KF, Stern DF. ErbB2 is required for ductal morphogenesis of the mammary gland. Proc Natl Acad Sci USA 2004;101(49):17138–43.

    PubMed  CAS  Google Scholar 

  26. Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 1984;307(5951):521–7.

    PubMed  CAS  Google Scholar 

  27. Bargmann CI, Hung MC, Weinberg RA. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature 1986;319(6050):226–30.

    PubMed  CAS  Google Scholar 

  28. Marmor MD, Yarden Y. Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 2004;23(11):2057–70.

    PubMed  CAS  Google Scholar 

  29. Roskoski R, Jr. The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun 2004;319(1):1–11.

    PubMed  CAS  Google Scholar 

  30. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer 2001;37(Suppl 4):S9–15.

    PubMed  CAS  Google Scholar 

  31. Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM. Expression of the HER1–4 family of receptor tyrosine kinases in breast cancer. J Pathol 2003;200(3):290–7.

    PubMed  CAS  Google Scholar 

  32. Tovey SM, Witton CJ, Bartlett JM, Stanton PD, Reeves JR, Cooke TG. Outcome and human epidermal growth factor receptor (HER) 1–4 status in invasive breast carcinomas with proliferation indices evaluated by bromodeoxyuridine labelling. Breast Cancer Res 2004;6(3):R246–51.

    PubMed  CAS  Google Scholar 

  33. Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol 2004;44:195–217.

    PubMed  CAS  Google Scholar 

  34. Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 2000;60(5):1383–7.

    PubMed  CAS  Google Scholar 

  35. Kuan CT, Wikstrand CJ, Bigner DD. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer 2001;8(2):83–96.

    PubMed  CAS  Google Scholar 

  36. Abd El-Rehim DM, Pinder SE, Paish CE, Bell JA, Rampaul RS, Blamey RW, Robertson JF, Nicholson RI, Ellis IO. Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma. Br J Cancer 2004;91(8):1532–42.

    PubMed  CAS  Google Scholar 

  37. Jungbluth AA, Stockert E, Huang HJ, Collins VP, Coplan K, Iversen K, Kolb D, Johns TJ, Scott AM, Gullick WJ, Ritter G, Cohen L, Scanlan MJ, Cavanee WK, Old LJ. A monoclonal antibody recognizing human cancers with amplification/overexpression of the human epidermal growth factor receptor. Proc Natl Acad Sci USA 2003;100(2):639–44.

    PubMed  CAS  Google Scholar 

  38. Rae JM, Scheys JO, Clark KM, Chadwick RB, Kiefer MC, Lippman ME. EGFR and EGFRvIII expression in primary breast cancer and cell lines. Breast Cancer Res Treat 2004;87(1): 87–95.

    PubMed  CAS  Google Scholar 

  39. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304(5676):1497–500.

    PubMed  CAS  Google Scholar 

  40. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129–39.

    PubMed  CAS  Google Scholar 

  41. Junttila TT, Laato M, Vahlberg T, Soderstrom KO, Visakorpi T, Isola J, Elenius K. Identification of patients with transitional cell carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR analysis in estimation of ErbB receptor status from cancer patients. Clin Cancer Res 2003;9(14):5346–57.

    PubMed  CAS  Google Scholar 

  42. Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, Symmans WF, Pusztai L, Bloom KJ. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 2003;8(4):307–25.

    PubMed  Google Scholar 

  43. Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, Stevens C, O'Meara S, Smith R, Parker A, Barthorpe A, Blow M, Brackenbury L, Butler A, Clarke O, Cole J, Dicks E, Dike A, Drozd A, Edwards K, Forbes S, Foster R, Gray K, Greenman C, Halliday K, Hills K, Kosmidou V, Lugg R, Menzies A, Perry J, Petty R, Raine K, Ratford L, Shepherd R, Small A, Stephens Y, Tofts C, Varian J, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Knowles M, Leung SY, Louis DN, Looijenga LH, Malkowicz B, Pierotti MA, Teh B, Chenevix-Trench G, Weber BL, Yuen ST, Harris G, Goldstraw P, Nicholson AG, Futreal PA, Wooster R, Stratton MR. Lung cancer: intragenic EerB2 kinase mutations in tumours. Nature 2004;431(7008):525–6.

    PubMed  CAS  Google Scholar 

  44. Castiglioni F, Tagliabue E, Campiglio M, Pupa SM, Balsari A, Menard S. Role of exon-16-deleted HER2 in breast carcinomas. Endocr Relat Cancer 2006;13(1) 221–32.

    PubMed  CAS  Google Scholar 

  45. Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P. Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 1988;54(1):105–15.

    PubMed  CAS  Google Scholar 

  46. Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 1992;89(22):10578–82.

    PubMed  CAS  Google Scholar 

  47. Siegel PM, Dankort DL, Hardy WR, Muller WJ. Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. Mol Cell Biol 1994;14(11):7068–77.

    PubMed  CAS  Google Scholar 

  48. Siegel PM, Ryan ED, Cardiff RD, Muller WJ. Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J 1999;18(8):2149–64.

    PubMed  CAS  Google Scholar 

  49. Lemoine NR, Barnes DM, Hollywood DP, Hughes CM, Smith P, Dublin E, Prigent SA, Gullick WJ, Hurst HC. Expression of the ErbB3 gene product in breast cancer. Br J Cancer 1992;66(6):1116–21.

    PubMed  CAS  Google Scholar 

  50. Naidu R, Yadav M, Nair S, Kutty MK. Expression of c-ErbB3 protein in primary breast carcinomas. Br J Cancer 1998;78(10):1385–90.

    PubMed  CAS  Google Scholar 

  51. Wiseman SM, Makretsov N, Nielsen TO, Gilks B, Yorida E, Cheang M, Turbin D, Gelmon K, Huntsman DG. Coexpression of the type 1 growth factor receptor family members HER-1, HER-2, and HER-3 has a synergistic negative prognostic effect on breast carcinoma survival. Cancer 2005;103(9):1770–7.

    PubMed  CAS  Google Scholar 

  52. Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, Di Fiore PP, Kraus MH. Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 1995;10(9):1813–21.

    PubMed  CAS  Google Scholar 

  53. Earp HS, III, Calvo BF, Sartor CI. The EGF receptor family-multiple roles in proliferation, differentiation, and neoplasia with an emphasis on HER4. Trans Am Clin Climatol Assoc 2003;114:315–33.

    PubMed  Google Scholar 

  54. Gilbertson R, Hernan R, Pietsch T, Pinto L, Scotting P, Allibone R, Ellison D, Perry R, Pearson A, Lunec J. Novel ErbB4 juxtamembrane splice variants are frequently expressed in childhood medulloblastoma. Genes Chromosomes Cancer 2001;31(3):288–94.

    PubMed  CAS  Google Scholar 

  55. Gilbertson RJ, Perry RH, Kelly PJ, Pearson AD, Lunec J. Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res 1997;57(15):3272–80.

    PubMed  CAS  Google Scholar 

  56. Sartor CI, Zhou H, Kozlowska E, Guttridge K, Kawata E, Caskey L, Harrelson J, Hynes N, Ethier S, Calvo B, Earp HS, 3rd. HER4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol 2001;21(13):4265–75.

    PubMed  CAS  Google Scholar 

  57. Williams EE, Trout LJ, Gallo RM, Pitfield SE, Bryant I, Penington DJ, Riese DJ, 2nd. A constitutively active ErbB4 mutant inhibits drug-resistant colony formation by the DU-145 and PC-3 human prostate tumor cell lines. Cancer Lett 2003;192(1):67–74.

    PubMed  CAS  Google Scholar 

  58. Suo Z, Risberg B, Kalsson MG, Willman K, Tierens A, Skovlund E, Nesland JM. EGFR family expression in breast carcinomas. c-ErbB-2 and c-ErbB-4 receptors have different effects on survival. J Pathol 2002;196(1):17–25.

    PubMed  CAS  Google Scholar 

  59. Barnes NL, Khavari S, Boland GP, Cramer A, Knox WF, Bundred NJ. Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast. Clin Cancer Res 2005;11(6):2163–8.

    PubMed  CAS  Google Scholar 

  60. Soung YH, Lee JW, Kim SY, Wang YP, Jo KH, Moon SW, Park WS, Nam SW, Lee JY, Yoo NJ, Lee SH. Somatic mutations of the ErbB4 kinase domain in human cancers. Int J Cancer 2006;118(6):1426–9.

    PubMed  CAS  Google Scholar 

  61. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659–72.

    PubMed  CAS  Google Scholar 

  62. Sweeney C, Carraway KL, III. Negative regulation of ErbB family receptor tyrosine kinases. Br J Cancer 2004;90(2):289–93.

    PubMed  CAS  Google Scholar 

  63. Doherty JK, Bond C, Jardim A, Adelman JP, Clinton GM. The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc Natl Acad Sci USA 1999;96(19):10869–74.

    PubMed  CAS  Google Scholar 

  64. Azios NG, Romero FJ, Denton MC, Doherty JK, Clinton GM. Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor. Oncogene 2001;20(37):5199–209.

    PubMed  CAS  Google Scholar 

  65. Justman QA, Clinton GM. Herstatin, an autoinhibitor of the human epidermal growth factor receptor 2 tyrosine kinase, modulates epidermal growth factor signaling pathways resulting in growth arrest. J Biol Chem 2002;277(23):20618–24.

    PubMed  CAS  Google Scholar 

  66. Jhabvala-Romero F, Evans A, Guo S, Denton M, Clinton GM. Herstatin inhibits heregulin-mediated breast cancer cell growth and overcomes tamoxifen resistance in breast cancer cells that overexpress HER-2. Oncogene 2003;22(50):8178–86.

    PubMed  CAS  Google Scholar 

  67. Shamieh LS, Evans AJ, Denton MC, Clinton GM. Receptor binding specificities of Herstatin and its intron 8-encoded domain. FEBS Lett 2004;568(1–3):163–6.

    PubMed  CAS  Google Scholar 

  68. Hu P, Feng J, Zhou T, Wang J, Jing B, Yu M, Hu M, Zhang X, Shen B, Guo N. In vivo identification of the interaction site of ErbB2 extracellular domain with its autoinhibitor. J Cell Physiol 2005;205(3):335–43.

    PubMed  CAS  Google Scholar 

  69. Staverosky JA, Muldoon LL, Guo S, Evans AJ, Neuwelt EA, Clinton GM. Herstatin, an autoinhibitor of the epidermal growth factor receptor family, blocks the intracranial growth of glioblastoma. Clin Cancer Res 2005;11(1):335–40.

    PubMed  CAS  Google Scholar 

  70. Dikic I, Giordano S. Negative receptor signalling. Curr Opin Cell Biol 2003;15(2):128–35.

    PubMed  CAS  Google Scholar 

  71. Fiorini M, Alimandi M, Fiorentino L, Sala G, Segatto O. Negative regulation of receptor tyrosine kinase signals. FEBS Lett 2001;490(3):132–41.

    PubMed  CAS  Google Scholar 

  72. Fiorentino L, Pertica C, Fiorini M, Talora C, Crescenzi M, Castellani L, Alema S, Benedetti P, Segatto O. Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain. Mol Cell Biol 2000;20(20):7735–50.

    PubMed  CAS  Google Scholar 

  73. Hackel PO, Gishizky M, Ullrich A. Mig-6 is a negative regulator of the epidermal growth factor receptor signal. Biol Chem 2001;382(12):1649–62.

    PubMed  CAS  Google Scholar 

  74. Anastasi S, Fiorentino L, Fiorini M, Fraioli R, Sala G, Castellani L, Alema S, Alimandi M, Segatto O. Feedback inhibition by RALT controls signal output by the ErbB network. Oncogene 2003;22(27):4221–34.

    PubMed  CAS  Google Scholar 

  75. Xu D, Makkinje A, Kyriakis JM. Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. J Biol Chem 2005;280(4):2924–33.

    PubMed  CAS  Google Scholar 

  76. Anastasi S, Sala G, Huiping C, Caprini E, Russo G, Iacovelli S, Lucini F, Ingvarsson S, Segatto O. Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin. Oncogene 2005;24(28):4540–8.

    PubMed  CAS  Google Scholar 

  77. Ballaro C, Ceccarelli S, Tiveron C, Tatangelo L, Salvatore AM, Segatto O, Alema S. Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype. EMBO Rep 2005;6(8):755–61.

    PubMed  CAS  Google Scholar 

  78. Shilo BZ. Signaling by the Drosophila epidermal growth factor receptor pathway during development. Exp Cell Res 2003;284(1):140–9.

    PubMed  CAS  Google Scholar 

  79. Kim HJ, Bar-Sagi D. Modulation of signalling by Sprouty: a developing story. Nat Rev Mol Cell Biol 2004;5(6):441–50.

    PubMed  CAS  Google Scholar 

  80. Klein DE, Nappi VM, Reeves GT, Shvartsman SY, Lemmon MA. Argos inhibits epidermal growth factor receptor signalling by ligand sequestration. Nature 2004;430(7003):1040–4.

    PubMed  CAS  Google Scholar 

  81. Musacchio M, Perrimon N. The Drosophila kekkon genes: novel members of both the leucine-rich repeat and immunoglobulin superfamilies expressed in the CNS. Dev Biol 1996;178(1):63–76.

    PubMed  CAS  Google Scholar 

  82. Ghiglione C, Carraway KL, III, Amundadottir LT, Boswell RE, Perrimon N, Duffy JB. The transmembrane molecule Kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis. Cell 1999;96(6):847–56.

    PubMed  CAS  Google Scholar 

  83. Alvarado D, Rice AH, Duffy JB. Knockouts of Kekkon1 define sequence elements essential for Drosophila epidermal growth factor receptor inhibition. Genetics 2004;166(1):201–11.

    PubMed  CAS  Google Scholar 

  84. MacLaren CM, Evans TA, Alvarado D, Duffy JB. Comparative analysis of the Kekkon molecules, related members of the LIG superfamily. Dev Genes Evol 2004;214(7):360–6.

    PubMed  CAS  Google Scholar 

  85. Ghiglione C, Amundadottir L, Andresdottir M, Bilder D, Diamonti JA, Noselli S, Perrimon N, Carraway, KL, III. Mechanism of inhibition of the Drosophila and mammalian EGF receptors by the transmembrane protein Kekkon 1. Development 2003;130(18):4483–93.

    PubMed  CAS  Google Scholar 

  86. Csordas G, Santra M, Reed CC, Eichstetter I, McQuillan DJ, Gross D, Nugent MA, Hajnoczky G, Iozzo RV. Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo. J Biol Chem 2000;275(42):32879–87.

    PubMed  CAS  Google Scholar 

  87. Santra M, Eichstetter I, Iozzo RV. An anti-oncogenic role for decorin. Down-regulation of ErbB2 leads to growth suppression and cytodifferentiation of mammary carcinoma cells. J Biol Chem 2000;275(45):35153–61.

    PubMed  CAS  Google Scholar 

  88. Zhu JX, Goldoni S, Bix G, Owens RT, McQuillan DJ, Reed CC, Iozzo RV. Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis. J Biol Chem 2005;280(37):32468–79.

    PubMed  CAS  Google Scholar 

  89. Santra M, Reed CC, Iozzo RV. Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope. J Biol Chem 2002;277(38):35671–81.

    PubMed  CAS  Google Scholar 

  90. Reed CC, Waterhouse A, Kirby S, Kay P, Owens RT, McQuillan DJ, Iozzo RV. Decorin prevents metastatic spreading of breast cancer. Oncogene 2005;24(6):1104–10.

    PubMed  CAS  Google Scholar 

  91. Guo D, Holmlund C, Henriksson R, Hedman H. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 2004;84(1):157–65.

    PubMed  CAS  Google Scholar 

  92. Nilsson J, Vallbo C, Guo D, Golovleva I, Hallberg B, Henriksson R, Hedman H. Cloning, characterization, and expression of human LIG1. Biochem Biophys Res Commun 2001;284(5):1155–61.

    PubMed  CAS  Google Scholar 

  93. Suzuki Y, Miura H, Tanemura A, Kobayashi K, Kondoh G, Sano S, Ozawa K, Inui S, Nakata A, Takagi T, Tohyama M, Yoshikawa K, Itami S. Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia. FEBS Lett 2002;521(1–3):67–71.

    PubMed  CAS  Google Scholar 

  94. Nilsson J, Starefeldt A, Henriksson R, Hedman H. LRIG1 protein in human cells and tissues. Cell Tissue Res 2003;312(1):65–71.

    PubMed  CAS  Google Scholar 

  95. Hedman H, Nilsson J, Guo D, Henriksson R. Is LRIG1 a tumour suppressor gene at chromosome 3p14.3? Acta Oncol 2002;41(4):352–4.

    PubMed  CAS  Google Scholar 

  96. Thomasson M, Hedman H, Guo D, Ljungberg B, Henriksson R. LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT-PCR and immunohistochemical analysis. Br J Cancer 2003;89(7):1285–9.

    PubMed  CAS  Google Scholar 

  97. Tanemura A, Nagasawa T, Inui S, Itami S. LRIG-1 provides a novel prognostic predictor in squamous cell carcinoma of the skin: immunohistochemical analysis for 38 cases. Dermatol Surg 2005;31(4):423–30.

    PubMed  CAS  Google Scholar 

  98. Maitra A, Wistuba, II, Washington C, Virmani AK, Ashfaq R, Milchgrub S, Gazdar AF, Minna JD. High-resolution chromosome 3p allelotyping of breast carcinomas and precursor lesions demonstrates frequent loss of heterozygosity and a discontinuous pattern of allele loss. Am J Pathol 2001;159(1):119–30.

    PubMed  CAS  Google Scholar 

  99. Ljuslinder I, Malmer B, Golovleva I, Thomasson M, Grankvist K, Hockenstrom T, Emdin S, Jonsson Y, Hedman H, Henriksson R. Increased copy number at 3p14 in breast cancer. Breast Cancer Res 2005;7(5):R719–27.

    PubMed  CAS  Google Scholar 

  100. Cook PW, Piepkorn M, Clegg CH, Plowman GD, DeMay JM, Brown JR, Pittelkow MR. Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. J Clin Invest 1997;100(9):2286–94.

    PubMed  CAS  Google Scholar 

  101. Vassar R, Fuchs E. Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation. Genes Dev 1991;5(5):714–27.

    PubMed  CAS  Google Scholar 

  102. Gur G, Rubin C, Katz M, Amit I, Citri A, Nilsson J, Amariglio N, Henriksson R, Rechavi G, Hedman H, Wides R, Yarden Y. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J 2004;23(16):3270–81.

    PubMed  CAS  Google Scholar 

  103. Laederich MB, Funes-Duran M, Yen L, Ingalla E, Wu X, Carraway KL, III, Sweeney C. The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem 2004;279(45):47050–6.

    PubMed  CAS  Google Scholar 

  104. Wells A, Welsh JB, Lazar CS, Wiley HS, Gill GN, Rosenfeld MG. Ligand-induced transformation by a noninternalizing epidermal growth factor receptor. Science 1990;247(4945):962–4.

    PubMed  CAS  Google Scholar 

  105. Shtiegman K, Yarden Y. The role of ubiquitylation in signaling by growth factors: implications to cancer. Semin Cancer Biol 2003;13(1):29–40.

    PubMed  CAS  Google Scholar 

  106. Levkowitz G, Klapper LN, Tzahar E, Freywald A, Sela M, Yarden Y. Coupling of the c-Cbl protooncogene product to ErbB-1/EGF-receptor but not to other ErbB proteins. Oncogene 1996;12(5):1117–25.

    PubMed  CAS  Google Scholar 

  107. Waterman H, Katz M, Rubin C, Shtiegman K, Lavi S, Elson A, Jovin T, Yarden Y. A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling. EMBO J 2002;21(3):303–13.

    PubMed  CAS  Google Scholar 

  108. Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S, Iwai K, Reiss Y, Ciechanover A, Lipkowitz S, Yarden Y. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell 1999;4(6):1029–40.

    PubMed  CAS  Google Scholar 

  109. Haglund K, Sigismund S, Polo S, Szymkiewicz I, Di Fiore PP, Dikic I. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 2003;5(5):461–6.

    PubMed  CAS  Google Scholar 

  110. de Melker AA, van der Horst G, Borst J. Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment. J Biol Chem 2004;279(53):55465–73.

    PubMed  Google Scholar 

  111. Conner SD, Schmid SL. Differential requirements for AP-2 in clathrin-mediated endocytosis. J Cell Biol 2003;162(5):773–9.

    PubMed  CAS  Google Scholar 

  112. Motley A, Bright NA, Seaman MN, Robinson MS. Clathrin-mediated endocytosis in AP-2-depleted cells. J Cell Biol 2003;162(5):909–18.

    PubMed  CAS  Google Scholar 

  113. Stang E, Blystad FD, Kazazic M, Bertelsen V, Brodahl T, Raiborg C, Stenmark H, Madshus IH. Cbl-dependent ubiquitination is required for progression of EGF receptors into clathrin-coated pits. Mol Biol Cell 2004;15(8):3591–604.

    PubMed  CAS  Google Scholar 

  114. Duan L, Miura Y, Dimri M, Majumder B, Dodge IL, Reddi AL, Ghosh A, Fernandes N, Zhou P, Mullane-Robinson K, Rao N, Donoghue S, Rogers RA, Bowtell D, Naramura M, Gu H, Band V, Band H. Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis. J Biol Chem 2003;278(31):28950–60.

    PubMed  CAS  Google Scholar 

  115. Ravid T, Heidinger JM, Gee P, Khan EM, Goldkorn T. c-Cbl-mediated ubiquitinylation is required for epidermal growth factor receptor exit from the early endosomes. J Biol Chem 2004;279(35):37153–62.

    PubMed  CAS  Google Scholar 

  116. Decker SJ. Epidermal growth factor and transforming growth factor-alpha induce differential processing of the epidermal growth factor receptor. Biochem Biophys Res Commun 1990;166(2):615–21.

    PubMed  CAS  Google Scholar 

  117. French AR, Tadaki DK, Niyogi SK, Lauffenburger DA. Intracellular trafficking of epidermal growth factor family ligands is directly influenced by the pH sensitivity of the receptor/ligand interaction. J Biol Chem 1995;270(9):4334–40.

    PubMed  CAS  Google Scholar 

  118. Ouyang X, Gulliford T, Huang G, Epstein RJ. Transforming growth factor-alpha short-circuits downregulation of the epidermal growth factor receptor. J Cell Physiol 1999;179(1):52–7.

    PubMed  CAS  Google Scholar 

  119. Waterman H, Alroy I, Strano S, Seger R, Yarden Y. The C-terminus of the kinase-defective neuregulin receptor ErbB-3 confers mitogenic superiority and dictates endocytic routing. EMBO J 1999;18(12):3348–58.

    PubMed  CAS  Google Scholar 

  120. Klapper LN, Waterman H, Sela M, Yarden Y. Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res 2000;60(13):3384–8.

    PubMed  CAS  Google Scholar 

  121. Levkowitz G, Oved S, Klapper LN, Harari D, Lavi S, Sela M, Yarden Y. c-Cbl is a suppressor of the neu oncogene. J Biol Chem 2000;275(45):35532–9.

    PubMed  CAS  Google Scholar 

  122. Magnifico A, Tagliabue E, Ardini E, Casalini P, Colnaghi MI, Menard S. Heregulin beta1 induces the down regulation and the ubiquitin-proteasome degradation pathway of p185HER2 oncoprotein. FEBS Lett 1998;422(2):129–31.

    PubMed  CAS  Google Scholar 

  123. Xu W, Marcu M, Yuan X, Mimnaugh E, Patterson C, Neckers L. Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu. Proc Natl Acad Sci USA 2002;99(20):12847–52.

    PubMed  CAS  Google Scholar 

  124. Wiley HS. Trafficking of the ErbB receptors and its influence on signaling. Exp Cell Res 2003;284(1):78–88.

    PubMed  CAS  Google Scholar 

  125. Katz M, Shtiegman K, Tal-Or P, Yakir L, Mosesson Y, Harari D, Machluf Y, Asao H, Jovin T, Sugamura K, Yarden Y. Ligand-independent degradation of epidermal growth factor receptor involves receptor ubiquitylation and Hgs, an adaptor whose ubiquitin-interacting motif targets ubiquitylation by Nedd4. Traffic 2002;3(10):740–51.

    PubMed  CAS  Google Scholar 

  126. Diamonti AJ, Guy PM, Ivanof C, Wong K, Sweeney C, Carraway KL, 3rd. An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels. Proc Natl Acad Sci USA 2002;99(5):2866–71.

    PubMed  CAS  Google Scholar 

  127. Qiu XB, Goldberg AL. Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3. Proc Natl Acad Sci USA 2002;99(23):14843–8.

    PubMed  CAS  Google Scholar 

  128. Wu X, Yen L, Irwin L, Sweeney C, Carraway KL, III. Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8. Mol Cell Biol 2004;24(17):7748–57.

    PubMed  CAS  Google Scholar 

  129. Arteaga CL. ErbB-targeted therapeutic approaches in human cancer. Exp Cell Res 2003;284(1):122–30.

    PubMed  CAS  Google Scholar 

  130. Mosesson Y, Yarden Y. Oncogenic growth factor receptors: implications for signal transduction therapy. Semin Cancer Biol 2004;14(4):262–70.

    PubMed  CAS  Google Scholar 

  131. Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell 2006;21(6):737–48.

    Google Scholar 

Download references

Acknowledgments

Colleen Sweeney is supported by NIH grant CA118384, and Kermit Carraway is supported by NIH grants GM068994 and CA123541. Jamie Miller is recipient of a DoD Breast Cancer Research Program predoctoral fellowship.

Author information

Affiliations

  1. UC Davis Cancer Center, Research Bldg. III, rm 1400, 4645 2nd Avenue, Sacramento, CA, 95817, USA

    Colleen Sweeney, Jamie K. Miller, David L. Shattuck & Kermit L. Carraway III

Authors
  1. Colleen Sweeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jamie K. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David L. Shattuck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kermit L. Carraway III
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Colleen Sweeney.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sweeney, C., Miller, J.K., Shattuck, D.L. et al. ErbB Receptor Negative Regulatory Mechanisms: Implications in Cancer. J Mammary Gland Biol Neoplasia 11, 89–99 (2006). https://doi.org/10.1007/s10911-006-9015-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-006-9015-3

Keywords

  • EGF receptor
  • Lrig1
  • Decorin
  • Kekkon1
  • Nrdp1
  • Herstatin
  • RALT
  • Cbl
  • Ubiquitin ligase
  • Trafficking