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.

Tight junction-based epithelial microenvironment and cell proliferation

“…This segregation provides one answer to the question of how ligand-receptor interactions are controlled in epithelia (Figure 4). In this respect, it was reported that airway epithelia constitutively produced both a ligand, the growth factor heregulin and its receptors, erbB2, erbB3 and erbB4 (Vermeer et al, 2003). However, in cases where TJs were formed, the ligand and receptors were segregated and the receptor activation was silenced.…”

“…However, in cases where TJs were formed, the ligand and receptors were segregated and the receptor activation was silenced. This model predicts that increased paracellular permeability as well as complete epithelial disruption would allow the ligand to access its receptors (Vermeer et al, 2003). This system has been recognized as a repair system for damage to epithelial layers (Chao et al, 2003).…”

The ERBB3 receptor in cancer and cancer gene therapy

“…366 In intact polarized human airway epithelium, NRG1 and ERBB3 were segregated, the former on the apical membrane, and the latter on the basolateral surface. 367 When the epithelium was disrupted, as in lung injury, NRG1 contacts and activates ERBB3 (and ERBB2). Cell division could then ensue to re-establish epithelial integrity.…”

The epithelial polarity program: machineries involved and their hijacking by cancer

“…A critical feature of polarized epithelia is the different compartmentalization of GFs to the basolateral side and receptors to the apical side, which prevents receptor activation. In one striking case, the loss of polarity of epithelial cells was shown to allow the intermixing of basolaterally localized HER2/ ErbB2, a member of the EGFR family and its activator heregulin, normally secreted to the apical side (Vermeer et al, 2003), leading to cell proliferation (Figure 4). Although this mechanism is responsible for wound healing of the respiratory epithelium in response to various types of aggression, it is not difficult to imagine the involvement of similar mechanisms in neoplastic transformation of epithelial cells.…”