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.

Segregation of receptor and ligand regulates activation of epithelial growth factor receptor

Nature volume 422, pages 322–326 (2003)Cite this article

Abstract

Interactions between ligands and receptors are central to communication between cells and tissues. Human airway epithelia constitutively produce both a ligand, the growth factor heregulin, and its receptors—erbB2, erbB3 and erbB4 (refs 1–3). Although heregulin binding initiates cellular proliferation and differentiation4,5,6,7, airway epithelia have a low rate of cell division8. This raises the question of how ligand–receptor interactions are controlled in epithelia. Here we show that in differentiated human airway epithelia, heregulin-α is present exclusively in the apical membrane and the overlying airway surface liquid, physically separated from erbB2–4, which segregate to the basolateral membrane. This physical arrangement creates a ligand–receptor pair poised for activation whenever epithelial integrity is disrupted. Indeed, immediately following a mechanical injury, heregulin-α activates erbB2 in cells at the edge of the wound, and this process hastens restoration of epithelial integrity. Likewise, when epithelial cells are not separated into apical and basolateral membranes (‘polarized’), or when tight junctions between adjacent cells are opened, heregulin-α activates its receptor. This mechanism of ligand–receptor segregation on either side of epithelial tight junctions may be vital for rapid restoration of integrity following injury, and hence critical for survival. This model also suggests a mechanism for abnormal receptor activation in diseases with increased epithelial permeability.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Figure 1: RT–PCR and western blots from primary cultures of human airway epithelia.
Figure 2: Immunostaining of erbB1-4 and heregulin-α in airway epithelia.
Figure 3: Involvement of ASL heregulin-α and erbB2 following mechanical wounding and repair of airway epithelia.
Figure 4: Immunostaining of phosphorylated erbB2.

References

  1. Aida, S., Tamai, S., Sekiguchi, S. & Shimizu, N. Distribution of epidermal growth factor and epidermal growth factor receptor in human lung: immunohistochemical and immunoelectron-microscopic studies. Respiration 61, 161–166 (1994)

    CAS  Article  Google Scholar 

  2. al Moustafa, A. E., Alaoui-Jamali, M., Paterson, J. & O'Connor-McCourt, M. Expression of P185erbB-2, P160erbB-3, P180erbB-4, and heregulin α in human normal bronchial epithelial and lung cancer cell lines. Anticancer Res. 19, 481–486 (1999)

    CAS  PubMed  Google Scholar 

  3. Polosa, R. et al. Expression of c-erbB receptors and ligands in human bronchial mucosa. Am. J. Respir. Cell Mol. Biol. 20, 914–923 (1999)

    CAS  Article  Google Scholar 

  4. van der Geer, P., Hunter, T. & Lindberg, R. A. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu. Rev. Cell Biol. 10, 251–337 (1994)

    CAS  Article  Google Scholar 

  5. Walker, R. A. The erbB/HER type 1 tyrosine kinase receptor family. J. Pathol. 185, 234–235 (1998)

    CAS  Article  Google Scholar 

  6. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001)

    CAS  Article  Google Scholar 

  7. Sweeney, C. et al. Growth factor-specific signaling pathway stimulation and gene expression mediated by ErbB receptors. J. Biol. Chem. 276, 22685–22698 (2001)

    CAS  Article  Google Scholar 

  8. Wang, G. et al. Influence of cell polarity on retrovirus-mediated gene transfer to differentiated human airway epithelia. J. Virol. 72, 9818–9826 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Dempsey, P. J., Meise, K. S., Yoshitake, Y., Nishikawa, K. & Coffey, R. J. Apical enrichment of human EGF precursor in Madin-Darby canine kidney cells involves preferential basolateral ectodomain cleavage sensitive to a metalloprotease inhibitor. J. Cell Biol. 138, 747–758 (1997)

    CAS  Article  Google Scholar 

  10. Aguilar, Z. & Slamon, D. J. The transmembrane heregulin precursor is functionally active. J. Biol. Chem. 276, 44099–44107 (2001)

    CAS  Article  Google Scholar 

  11. Campiglio, M., Ali, S., Knyazev, P. G. & Ullrich, A. Characteristics of EGFR family-mediated HRG signals in human ovarian cancer. J. Cell. Biochem. 73, 522–532 (1999)

    CAS  Article  Google Scholar 

  12. Mostov, K. E., Verges, M. & Altschuler, Y. Membrane traffic in polarized epithelial cells. Curr. Opin. Cell Biol. 12, 483–490 (2000)

    CAS  Article  Google Scholar 

  13. Wodarz, A. Tumor suppressors: linking cell polarity and growth control. Curr. Biol. 10, R624–R626 (2000)

    CAS  Article  Google Scholar 

  14. Kennedy, S. M., Elwood, R. K., Wiggs, B. J., Pare, P. D. & Hogg, J. C. Increased airway mucosal permeability of smokers. Relationship to airway reactivity. Am. Rev. Respir. Dis. 129, 143–148 (1984)

    CAS  PubMed  Google Scholar 

  15. Sobonya, R. E. & Taussig, L. M. Quantitative aspects of lung pathology in cystic fibrosis. Am. Rev. Respir. Dis. 134, 290–295 (1986)

    CAS  PubMed  Google Scholar 

  16. Godfrey, R. W. Human airway epithelial tight junctions. Microsc. Res. Tech. 38, 488–499 (1997)

    CAS  Article  Google Scholar 

  17. Goto, Y. et al. Dislocation of E-cadherin in the airway epithelium during an antigen-induced asthmatic response. Am. J. Respir. Cell Mol. Biol. 23, 712–718 (2000)

    CAS  Article  Google Scholar 

  18. Karp, P. H. et al. in Epithelial Cell Culture Protocols (ed. Wise, C.) 115–137 (Humana, Totowa, New Jersey, 2002)

    Book  Google Scholar 

  19. Walters, R. W. et al. Adenovirus fiber disrupts CAR-mediated intercellular adhesion allowing virus escape. Cell 110, 789–799 (2002)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank P. Karp, P. Weber, J. Launspach, T. Nesselhauf, L. Panko, T. Mayhew and D. Vermeer for technical assistance. We appreciate the help of the Iowa Statewide Organ Procurement Organization. We also thank the University of Iowa In Vitro Models and Cell Culture Core (supported in part by the National Heart, Lung and Blood Institute (NHLBI), the Cystic Fibrosis Foundation, and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK)), and the University of Iowa Central Microscopy Research Facility. This work was supported by the NHLBI, the CFF, and the Howard Hughes Medical Institute. P.D.V. was supported by a K01 award from the NIDDK. M.J.W. is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, 52242, USA

    Paola D. Vermeer, Lisa A. Einwalter, Tatiana Rokhlina, Joseph Zabner & Michael J. Welsh

  2. Central Microscopy Research Facility, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, 52242, USA

    Thomas O. Moninger

  3. Department of Physiology and Biophysics, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, 52242, USA

    Michael J. Welsh

  4. University Hospitals of Cleveland, 11100 Euclid Avenue, 610 Wearn, LKSD 5067, Cleveland, Ohio, 44106, USA

    Jeffrey A. Kern

Authors
  1. Paola D. Vermeer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa A. Einwalter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas O. Moninger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tatiana Rokhlina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey A. Kern
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joseph Zabner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael J. Welsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael J. Welsh.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vermeer, P., Einwalter, L., Moninger, T. et al. Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 422, 322–326 (2003). https://doi.org/10.1038/nature01440

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01440

Further reading

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