title: Segregation of receptor and ligand regulates activation of epithelial growth factor receptor.
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 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-alpha 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-alpha 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-alpha 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.
authors.affiliation: Department of Internal Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Paola D
authors.initials: PD
authors.lastname: Vermeer
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Einwalter
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Moninger
authors.forename: Tatiana
authors.initials: T
authors.lastname: Rokhlina
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kern
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D016764:Cell Polarity; D002478:Cells, Cultured; D004553:Electric Conductivity; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D010539:Permeability; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology; D014132:Trachea; D014947:Wounds and Injuries / Q000378:metabolism / Q000473:pathology
chemical_list: D002118:Calcium; D066246:ErbB Receptors; D008024:Ligands; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; C117463:heregulin alpha; C087230:heregulin beta1