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

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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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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.

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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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Correspondence to Michael 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) doi:10.1038/nature01440

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