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

• Published in: Nature (London) Vol. 422; no. 6929; pp. 322 - 326
• Main Authors: Welsh, Michael J, Vermeer, Paola D, Einwalter, Lisa A, Moninger, Thomas O, Rokhlina, Tatiana, Kern, Jeffrey A, Zabner, Joseph
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 20.03.2003; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Calcium - metabolism; Cell Line; Cell Polarity; Cell receptors; Cell structures and functions; Cells; Cells, Cultured; Cellular biology; Electric Conductivity; Epithelial Cells - metabolism; Epithelial Cells - pathology; Fundamental and applied biological sciences. Psychology; Humans; Ligands; Lung - metabolism; Lung - pathology; Male; Miscellaneous; Molecular and cellular biology; Neuregulin-1 - genetics; Neuregulin-1 - metabolism; Permeability; Phosphorylation; Proteins; Rats; Rats, Sprague-Dawley; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Tight Junctions - metabolism; Tight Junctions - pathology; Tissues; Trachea; Wounds and Injuries - metabolism; Wounds and Injuries - pathology; Human; Cell proliferation; Polarization; Segregation; Injury; Lung; Plasma membrane; Cell division; Neuregulin; Receptor protein; Epithelium; Apical membrane
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature01440

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 differentiation, airway epithelia have a low rate of cell division. 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.