Signalling by the predominantly basolateral epithelial growth factor receptor (EGFR) is regulated by the apico-basal distribution of its ligands. As little is known about the distribution of the EGFR ligand betacellulin (BTC) in polarised epithelial cells, in this issue (p. ), Bhuminder Singh, Robert Coffey and colleagues used truncation mutants and site-directed mutagenesis in MDCK cells to gain a better understanding of BTC function. They found that BTC was preferentially sorted to the basolateral membrane but was redistributed to both apical and basolateral surfaces upon deletion of its cytoplasmic domain. The authors also defined a monoleucine EExxxL motif that was necessary for the preferential basolateral targeting of BTC. Unlike missorting of other EGFR ligands, mistrafficking of BTC increased the number and area of lateral lumens. However, the architecture of these lateral lumens was not affected by missorting of BTC; they were positive for apical proteins and negative for basolateral proteins, and contained microvilli and primary cilia. Notably, lumen formation was significantly attenuated if EGFR was inhibited. The authors then tested the localisation of BTC that contained a cancer-associated E156K mutation, and found that it also lost its preference for basolateral membranes and increased the formation of lateral lumens. Finally, cells overexpressing a mistargeted BTC mutant had a growth advantage, further highlighting an important and unique role for BTC in EGFR-mediated reorganisation of epithelia.
