NE-dlg, a mammalian homolog of Drosophila DLG tumor suppressor, induces growth suppression and impairment of cell adhesion: Possible involvement of down-regulation of beta-catenin by NE-dlg expression

Membrane-associated guanylate kinases (MAGUKs) are known to function as sca ffolds for forming multiprotein complexes at the synaptic junctions of neur onal cells and at sites of epithelial cell-cell contact. In Drosophila, mut ations of the lethal (I)-discs large (dlg) gene, which encodes a MAGUK prot ein, leads to post-synaptic structure defects in neuronal cells and neoplas tic overgrowth of epithelial cells. We previously showed that HE-dig (neuro nal and endocrine dig), a human homolog of the dig, plays a crucial role in formation of synaptic structure in human neuronal cells. Here we demonstra te that HE-dig, similar to Drosophila dig, is involved in regulation of cel l cycle progression and adhesive ability of non-neuronal cells. Overexpress ion of HE-dig in proliferating cells including various cancer cell lines in duced growth suppression and impairment of cell adhesive ability. Furthermo re, HE-dig overexpression caused the down-regulation of beta-catenin in can cer cells regardless of mutations in the APC (adenomatous polyposis coli) g ene. The PDZ domains of HE-dig were found to be essential for the growth su ppression, loss of adhesive property and down-regulation of beta-catenin. W e propose that HE-dig regulates the cell growth and adhesive ability by con trolling the level of beta-catenin through an APC-independent pathway. Inac tivation of HE-dig may therefore contribute to development and/or progressi on of human neoplasms. Int. J. Cancer 86:480-488, 2000. (C) 2000 Wiley-Liss , Inc.