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.

  • Letter
  • Published:

ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor

Nature volume 461, pages 287–291 (2009)Cite this article

Abstract

The orphan receptor tyrosine kinase ErbB2 (also known as HER2 or Neu) transforms cells when overexpressed1, and it is an important therapeutic target in human cancer2,3. Structural studies4,5 have suggested that the oncogenic (and ligand-independent) signalling properties of ErbB2 result from the absence of a key intramolecular ‘tether’ in the extracellular region that autoinhibits other human ErbB receptors, including the epidermal growth factor (EGF) receptor6. Although ErbB2 is unique among the four human ErbB receptors6,7, here we show that it is the closest structural relative of the single EGF receptor family member in Drosophila melanogaster (dEGFR). Genetic and biochemical data show that dEGFR is tightly regulated by growth factor ligands8, yet a crystal structure shows that it, too, lacks the intramolecular tether seen in human EGFR, ErbB3 and ErbB4. Instead, a distinct set of autoinhibitory interdomain interactions hold unliganded dEGFR in an inactive state. All of these interactions are maintained (and even extended) in ErbB2, arguing against the suggestion that ErbB2 lacks autoinhibition. We therefore suggest that normal and pathogenic ErbB2 signalling may be regulated by ligands in the same way as dEGFR. Our findings have important implications for ErbB2 regulation in human cancer, and for developing therapeutic approaches that target novel aspects of this orphan receptor.

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: Autoinhibition of ErbB receptors.
Figure 2: The unactivated dEGFR extracellular region closely resembles sErbB2.
Figure 3: Ligand binding breaks autoinhibitory interactions between domains I and II common to s-dEGFR, s-hEGFR and sErbB2.

Similar content being viewed by others

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The structure for s-dEGFRΔV has been deposited in the Protein Data Bank under accession number 3I2T.

References

  1. Di Fiore, P. P. et al. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237, 178–182 (1987)

    Article  ADS  CAS  Google Scholar 

  2. Hynes, N. E. & Lane, H. A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Rev. Cancer 5, 341–354 (2005)

    Article  CAS  Google Scholar 

  3. Moasser, M. M. Targeting the function of the HER2 oncogene in human cancer therapeutics. Oncogene 26, 6577–6592 (2007)

    Article  CAS  Google Scholar 

  4. Cho, H. S. et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421, 756–760 (2003)

    Article  ADS  CAS  Google Scholar 

  5. Garrett, T. P. et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cell 11, 495–505 (2003)

    Article  CAS  Google Scholar 

  6. Burgess, A. W. et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 12, 541–552 (2003)

    Article  CAS  Google Scholar 

  7. Citri, A., Skaria, K. B. & Yarden, Y. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp. Cell Res. 284, 54–65 (2003)

    Article  CAS  Google Scholar 

  8. Shilo, B. Z. Regulating the dynamics of EGF receptor signaling in space and time. Development 132, 4017–4027 (2005)

    Article  CAS  Google Scholar 

  9. Lemmon, M. A. Ligand-induced ErbB receptor dimerization. Exp. Cell Res. 315, 638–648 (2009)

    Article  CAS  Google Scholar 

  10. Garrett, T. P. et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell 110, 763–773 (2002)

    Article  CAS  Google Scholar 

  11. Ogiso, H. et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775–787 (2002)

    Article  CAS  Google Scholar 

  12. Bouyain, S., Longo, P. A., Li, S., Ferguson, K. M. & Leahy, D. J. The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Proc. Natl Acad. Sci. USA 102, 15024–15029 (2005)

    Article  ADS  CAS  Google Scholar 

  13. Klein, D. E., Nappi, V. M., Reeves, G. T., Shvartsman, S. Y. & Lemmon, M. A. Argos inhibits epidermal growth factor receptor signalling by ligand sequestration. Nature 430, 1040–1044 (2004)

    Article  ADS  CAS  Google Scholar 

  14. Schweitzer, R., Shaharabany, M., Seger, R. & Shilo, B. Z. Secreted Spitz triggers the DER signaling pathway and is a limiting component in embryonic ventral ectoderm determination. Genes Dev. 9, 1518–1529 (1995)

    Article  CAS  Google Scholar 

  15. Dawson, J. P., Bu, Z. & Lemmon, M. A. Ligand-induced structural transitions in ErbB receptor extracellular domains. Structure 15, 942–954 (2007)

    Article  CAS  Google Scholar 

  16. Dawson, J. P. et al. Epidermal growth factor receptor dimerization and activation require ligand-induced conformational changes in the dimer interface. Mol. Cell. Biol. 25, 7734–7742 (2005)

    Article  CAS  Google Scholar 

  17. Ferguson, K. M. et al. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol. Cell 11, 507–517 (2003)

    Article  CAS  Google Scholar 

  18. Mattoon, D., Klein, P., Lemmon, M. A., Lax, I. & Schlessinger, J. The tethered configuration of the EGF receptor extracellular domain exerts only a limited control of receptor function. Proc. Natl Acad. Sci. USA 101, 923–928 (2004)

    Article  ADS  CAS  Google Scholar 

  19. Walker, F. et al. CR1/CR2 interactions modulate the functions of the cell surface epidermal growth factor receptor. J. Biol. Chem. 279, 22387–22398 (2004)

    Article  CAS  Google Scholar 

  20. Cho, H. S. & Leahy, D. J. Structure of the extracellular region of HER3 reveals an interdomain tether. Science 297, 1330–1333 (2002)

    Article  ADS  CAS  Google Scholar 

  21. Ferguson, K. M., Darling, P. J., Mohan, M. J., Macatee, T. L. & Lemmon, M. A. Extracellular domains drive homo- but not hetero-dimerization of erbB receptors. EMBO J. 19, 4632–4643 (2000)

    Article  CAS  Google Scholar 

  22. Horan, T. et al. Binding of Neu differentiation factor with the extracellular domain of Her2 and Her3. J. Biol. Chem. 270, 24604–24608 (1995)

    Article  CAS  Google Scholar 

  23. Penuel, E., Akita, R. W. & Sliwkowski, M. X. Identification of a region within the ErbB2/HER2 intracellular domain that is necessary for ligand-independent association. J. Biol. Chem. 277, 28468–28473 (2002)

    Article  CAS  Google Scholar 

  24. Wehrman, T. S. et al. A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactions. Proc. Natl Acad. Sci. USA 103, 19063–19068 (2006)

    Article  ADS  CAS  Google Scholar 

  25. Berger, M. B., Mendrola, J. M. & Lemmon, M. A. ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FEBS Lett. 569, 332–336 (2004)

    Article  CAS  Google Scholar 

  26. Brennan, P. J., Kumagai, T., Berezov, A., Murali, R. & Greene, M. I. HER2/neu: mechanisms of dimerization/oligomerization. Oncogene 19, 6093–6101 (2000)

    Article  CAS  Google Scholar 

  27. Carraway, K. L., Ramsauer, V. P., Haq, B. & Carothers Carraway, C. A. Cell signaling through membrane mucins. BioEssays 25, 66–71 (2003)

    Article  Google Scholar 

  28. Miura, G. I. et al. Palmitoylation of the EGFR ligand Spitz by Rasp increases Spitz activity by restricting its diffusion. Dev. Cell 10, 167–176 (2006)

    Article  MathSciNet  CAS  Google Scholar 

  29. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)

    Article  Google Scholar 

  30. CCP4 (Collaborative Computational Project Number 4). The CCP4 suite: Programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994)

  31. Klein, D. E., Stayrook, S. E., Shi, F., Narayan, K. & Lemmon, M. A. Structural basis for EGFR ligand sequestration by Argos. Nature 453, 1271–1275 (2008)

    Article  ADS  CAS  Google Scholar 

  32. Svergun, D. I. Determination of the regularization parameter in indirect-transform methods using perceptual criteria. J. Appl. Crystallogr. 25, 495–503 (1992)

    Article  CAS  Google Scholar 

  33. Svergun, D. I. Restoring low resolution structure of biological macromolecules from solution scattering using simulated annealing. Biophys. J. 76, 2879–2886 (1999)

    Article  ADS  CAS  Google Scholar 

  34. Volkov, V. V. & Svergun, D. I. Uniqueness of ab initio shape determination in small-angle scattering. J. Appl. Crystallogr. 36, 860–864 (2003)

    Article  CAS  Google Scholar 

  35. Wriggers, W. & Birmanns, S. Using Situs for flexible and rigid-body fitting of multiresolution single-molecule data. J. Struct. Biol. 133, 193–202 (2001)

    Article  CAS  Google Scholar 

  36. Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004)

    Article  CAS  Google Scholar 

  37. Clifford, R. & Schupbach, T. Molecular analysis of the Drosophila EGF receptor homolog reveals that several genetically defined classes of alleles cluster in subdomains of the receptor protein. Genetics 137, 531–550 (1994)

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Lesokhin, A. M., Yu, S. Y., Katz, J. & Baker, N. E. Several levels of EGF receptor signaling during photoreceptor specification in wild-type, Ellipse, and null mutant Drosophila . Dev. Biol. 205, 129–144 (1999)

    Article  CAS  Google Scholar 

  39. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

    Article  CAS  Google Scholar 

  40. Brunger, A. T. et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998)

    Article  CAS  Google Scholar 

  41. Winn, M. D., Isupov, M. N. & Murshudov, G. N. Use of TLS anisotropic displacements in macromolecular refinement. Acta Crystallogr. D 57, 122–133 (2001)

    Article  CAS  Google Scholar 

  42. Lawrence, M. C. & Colman, P. M. Shape complementarity at protein/protein interfaces. J. Mol. Biol. 234, 946–950 (1993)

    Article  CAS  Google Scholar 

  43. DeLano, W. L. The PyMOL Molecular Graphics System (DeLano Scientific, 2002)

    Google Scholar 

Download references

Acknowledgements

We thank members of the Lemmon and Ferguson laboratories, K. Ferguson, G. Van Duyne, C. Abrams and J. Shorter for advice and comments on the manuscript; Z. Bu for assistance with collecting SAXS data; and R. Gillilan of MacCHESS for help with SAXS data collection and processing at CHESS beamline G1. Crystallographic results were obtained in research conducted at the GM/CA Collaborative Access Team at the Advanced Photon Source (APS), supported with funds from the National Cancer Institute and National Institute of General Medical Science. This study was supported by grants from the NIH (to M.A.L.). D.E.K. was supported by a Predoctoral fellowship from the US Army Breast Cancer Research Program. D.A. was supported by an NIH Postdoctoral Training Grant and a Postdoctoral Fellowship from the Damon Runyon Cancer Research Foundation.

Author Contributions D.A., D.E.K. and M.A.L. conceived and designed the project. D.E.K. established initial expression and purification procedures for s-dEGFR variants and relevant ligands. D.A. was responsible for designing s-dEGFR constructs used in this study and executed all biophysical studies, crystallization and data collection. D.A. also solved and refined the s-dEGFRΔV structure. D.A. and M.A.L. interpreted data and wrote the manuscript.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA,

    Diego Alvarado, Daryl E. Klein & Mark A. Lemmon

Authors
  1. Diego Alvarado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daryl E. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark A. Lemmon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark A. Lemmon.

Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-S7 with Legends, Supplementary Tables 1-3 and Supplementary References. (PDF 1114 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alvarado, D., Klein, D. & Lemmon, M. ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor. Nature 461, 287–291 (2009). https://doi.org/10.1038/nature08297

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08297

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing