Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling

Oncogene volume 26, pages 6968–6978 (2007)Cite this article

Abstract

Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Amann J, Kalyankrishna S, Massion PP, Ohm JE, Girard L, Shigematsu H et al. (2005). Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res 65: 226–235.

    CAS  PubMed  Google Scholar 

  • Baulida J, Kraus MH, Alimandi M, Di Fiore PP, Carpenter G . (1996). All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem 271: 5251–5257.

    Article  CAS  PubMed  Google Scholar 

  • Dikic I, Giordano S . (2003). Negative receptor signalling. Curr Opin Cell Biol 15: 128–135.

    Article  CAS  PubMed  Google Scholar 

  • Engelman JA, Janne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C et al. (2005). ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA 102: 3788–3793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedman LM, Rinon A, Schechter B, Lyass L, Lavi S, Bacus SS et al. (2005). Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: Implications for cancer immunotherapy. Proc Natl Acad Sci USA 102: 1915–1920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graus Porta D, Beerli RR, Daly JM, Hynes NE . (1997). ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16: 1647–1655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hynes NE, Horsch K, Olayioye MA, Badache A . (2001). The ErbB receptor tyrosine family as signal integrators. Endocr Relat Cancer 8: 151–159.

    Article  CAS  PubMed  Google Scholar 

  • Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus Porta D, Ratzkin BJ et al. (1996). ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 15: 254–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M et al. (2005). EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. New Engl J Med 352: 786–792.

    Article  CAS  PubMed  Google Scholar 

  • Kokai Y, Myers JN, Wada T, Brown VI, LeVea CM, Davis JG et al. (1989). Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts. Cell 58: 287–292.

    Article  CAS  PubMed  Google Scholar 

  • Levkowitz G, Klapper LN, Tzahar E, Freywald A, Sela M, Yarden Y . (1996). Coupling of the c-Cbl protooncogene product to ErbB-1/EGF-receptor but not to other ErbB proteins. Oncogene 12: 1117–1125.

    CAS  PubMed  Google Scholar 

  • Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I et al. (1999). Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell 4: 1029–1040.

    Article  CAS  PubMed  Google Scholar 

  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139.

    Article  CAS  PubMed  Google Scholar 

  • Marmor MD, Yarden Y . (2004). Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 23: 2057–2070.

    Article  CAS  PubMed  Google Scholar 

  • Muthuswamy SK, Gilman M, Brugge JS . (1999). Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol 19: 6845–6857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ouyang X, Gulliford T, Zhang H, Smith G, Huang G, Epstein RJ . (2001). Association of ErbB2 Ser1113 phosphorylation with epidermal growth factor receptor co-expression and poor prognosis in human breast cancer. Mol Cell Biochem 218: 47–54.

    Article  CAS  PubMed  Google Scholar 

  • Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500.

    Article  CAS  PubMed  Google Scholar 

  • Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I et al. (2004). EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101: 13306–13311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pao W, Miller VA, Politi KA, Rieli GJ, Somwar R, Zakowski MF et al. (2005). Acquired resistance of lung adenocarcinomas to Gefitinib or Erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Medicine 2: e73.

    Article  PubMed  PubMed Central  Google Scholar 

  • Polo S, Sigismund S, Faretta M, Guidi M, Capua MR, Bossi G et al. (2002). A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416: 451–455.

    Article  CAS  PubMed  Google Scholar 

  • Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P et al. (2005). Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci USA 102: 2760–2765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A et al. (1994). Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 269: 14661–14665.

    CAS  PubMed  Google Scholar 

  • Sordella R, Bell DW, Haber DA, Settleman J . (2004). Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305: 1163–1167.

    Article  CAS  PubMed  Google Scholar 

  • Tracy S, Mukohara T, Hansen M, Meyerson M, Johnson BE, Janne PA . (2004). Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 64: 7241–7244.

    Article  CAS  PubMed  Google Scholar 

  • Waterman H, Alroy I, Strano S, Seger R, Yarden Y . (1999). The C-terminus of the kinase-defective neuregulin receptor ErbB-3 confers mitogenic superiority and dictates endocytic routing. EMBO J 18: 3348–3358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waterman H, Katz M, Rubin C, Shtiegman K, Lavi S, Elson A et al. (2002). A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling. EMBO J 21: 303–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wells A, Welsh JB, Lazar CS, Wiley HS, Gill GN, Rosenfeld MG . (1990). Ligand-induced transformation by a non-internalizing epidermal growth factor receptor. Science 247: 962–964.

    Article  CAS  PubMed  Google Scholar 

  • Wiley HS, Burke PM . (2001). Regulation of receptor tyrosine kinase signaling by endocytic trafficking. Traffic 2: 12–18.

    Article  CAS  PubMed  Google Scholar 

  • Worthylake R, Opresko LK, Wiley HS . (1999). ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem 274: 8865–8874.

    Article  CAS  PubMed  Google Scholar 

  • Yang S, Qu S, Perez-Tores M, Sawai A, Rosen N, Solit DB et al. (2006). Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors. Cancer Res 66: 6990–6997.

    Article  CAS  PubMed  Google Scholar 

  • Yarden Y, Sliwkowski MX . (2001). Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2: 127–137.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Drs Wallace Langdon and Dirk Bohmann for plasmids. Our laboratory is supported by research grants from the National Cancer Institute (grant CA72981, to YY), the Israel Cancer Research Fund and the German-Israel Foundation. YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair.

Author information

Authors and Affiliations

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel

    K Shtiegman, B S Kochupurakkal, Y Zwang, G Pines, A Citri, M Katz, S Lavi, Y Ben-Basat, J Gan & Y Yarden

  2. Division of Oncology, Tel Aviv Sourasky Medical Center and Tel Aviv University School of Medicine, Ramat Aviv, Israel

    A Starr, A Vexler & R B Yosef

  3. Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, Israel

    S Benjamin

  4. Division of Molecular Oncology, Department of Oncological Sciences, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Candiolo, Torino, Italy

    S Corso & S Giordano

Authors
  1. K Shtiegman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B S Kochupurakkal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Zwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Pines
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Starr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Vexler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Citri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Katz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Lavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Y Ben-Basat
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Benjamin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S Corso
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. R B Yosef
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. S Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Y Yarden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Yarden.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shtiegman, K., Kochupurakkal, B., Zwang, Y. et al. Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling. Oncogene 26, 6968–6978 (2007). https://doi.org/10.1038/sj.onc.1210503

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210503

Keywords

This article is cited by

Search

Advanced search

Quick links