Wound repair: Closure brings healing

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Growth regulation of epithelial cells and wound repair is controlled by tight junctions segregating the growth factor heregulin on the apical membrane from its receptors on the basolateral membrane.

The epithelial monolayer represents the body's first line of defence against invasion of bacteria or toxins in the digestive and respiratory systems. Comprised of polarized epithelial cells, any damage to this barrier must be quickly repaired, but exactly how the signaling cascades that control this function operate remains unclear.

Epithelial cells produce both growth factor receptors, such as the erbB family of receptors, and their ligands, including heregulin, epidermal growth factor and TGF- alpha . Ligand binding results in the phosphorylation of erbB, activating signaling cascades that lead to cellular differentiation and proliferation. However, despite expressing both ligand and receptor on the same cell, mitogenic signaling is not observed in normal epithelial cells.

Michael Welsh and colleagues investigated this selective interaction, and show that airway epithelia express the growth factor heregulin- alpha and its erbB receptor on distinct sides of the polarized epithelial cell in vivo. Heregulin- alpha is localized to the apical membrane, which faces the airway side of the organ, and is released into the airway surface liquid (ASL). erbB receptors, on the other hand, were found only at the basolateral membrane, which faces adjacent cells and underlying tissue.

Because of this segregation of receptor and ligand to opposite sides of the epithelium, the authors reasoned that adding heregulin- alpha to the basolateral side of the cells would activate erbB2, which proved correct. To determine if tight junctions, which link adjacent membranes and play a central role in controlling the permeability of epithelia, are responsible for segregating the ligand from its receptors, the group disrupted the junctions by Ca²⁺ chelation. On the apical domain they then added heregulin- alpha , which led to erbB2 and erbB3 activation, showing that tight junctions separate ALS heregulin- alpha from receptors on the basolateral surface. Welsh's group then noted that by mechanically injuring epithelia, the differentiation and proliferation of cells necessary to repair the injury occurred only when neither the heregulin- alpha ligand nor the erbB receptors were inhibited. Preventing the tight junctions from functioning by removing extra-cellular calcium also resulted in cell proliferation.

Aside from wound healing, this involvement of tight junctions in cell proliferation has wide-ranging implications in development and in cancer. This finding also provides an interesting example of how compartmentalizing signaling components within a cell can lead to very different signaling outcomes.

Julia Howlett, Assistant Editor
Signaling Gateway

References

Vermeer, Paola D. Lisa, Einwalter A. Moninger, Thomas O. Tatiana, Rokhlina Kern, Jeffrey A. Zabner, Joseph Welsh, Michael J. Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature, 422, 322–326 (2003) 10.1038/ni893
Mostov, Keith Zegers, Mirjam Cell biology: Just mix and patch. Nature, 422, 267–268 (March 2003) 10.1038/ni893 | PubMed |