ErbB-2/HER2 drives epithelial malignancies by forming heterodimers with growth factor receptors. The primordial invertebrate receptor is sorted to the basolateral epithelial surface by binding of the PDZ domain of Lin-7 to the receptor's tail. We show that all four human ErbBs are basolaterally expressed, even when the tail motif is absent. Mutagenesis of hLin-7 unveiled a second domain, KID, that binds to the kinase region of ErbBs. The PDZ interaction mediates stabilization of ErbB-2 at the basolateral surface. On the other hand, binding of KID is involved in initial delivery to the basolateral surface, and in its absence, unprocessed ErbB-2 molecules are diverted to the apical surface. Hence, distinct domains of Lin-7 regulate receptor delivery to and maintenance at the basolateral surface of epithelia.
Bibliographical noteFunding Information:
We thank Drs. Borg and Birnboim for plasmids; Dr. Ena Orzech for advice; and the microscopy unit of the Hebrew University for immunofluorescence. This work was supported in part by grants from the National Cancer Institute (grant CA72981), the European Community (grant QLG1-2000-02160), the United States-Israel Binational Science Foundation (grant 1999-277), and the Israel Science Foundation funded by the Israel Academy of Sciences.