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

Abstract

Membrane-associated guanylate kinases (MAGUK's) are known to function as scaffolds for forming multiprotein complexes at the synaptic junctions of neuronal cells and at sites of epithelial cell-cell contact. In Drosophila, mutations of the lethal (I)-discs large (dig) gene, which encodes a MAGUK protein, leads to post-synaptic structure defects in neuronal cells and neoplastic overgrowth of epithelial cells. We previously showed that NE-dig (neuronal and endocrine dig), a human homolog of the dig, plays a crucial role in formation of synaptic structure in human neuronal cells. Here we demonstrate that NE-dig, similar to Drosophila dig, is involved in regulation of cell cycle progression and adhesive ability of non-neuronal cells. Overexpression of NE-dlg in proliferating cells including various cancer cell lines induced growth suppression and impairment of cell adhesive ability. Furthermore, NE-dlg overexpression caused the down-regulation of β-catenin in cancer cells regardless of mutations in the APC (adenomatous polyposis coil) gene. The PDZ domains of NE-dlg were found to be essential for the growth suppression, loss of adhesive property and down-regulation of β- catenin. We propose that NE-dlg regulates the cell growth and adhesive ability by controlling the level of β-catenin through an APC-independent pathway. Inactivation of NE-dlg may therefore contribute to development and/or progression of human neoplasms. (C) 2000 Wiley-Liss, Inc.