Segregation of receptor and ligand regulates activation of epithelial growth factor receptor (original) (raw)

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.

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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.

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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
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  2. Lisa A. Einwalter
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  3. Thomas O. Moninger
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  4. Tatiana Rokhlina
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  5. Jeffrey A. Kern
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  6. Joseph Zabner
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  7. Michael J. Welsh
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Correspondence toMichael J. Welsh.

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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

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