DYNAMICS OF BETA-CATENIN INTERACTIONS WITH APC PROTEIN REGULATE EPITHELIAL TUBULOGENESIS

Epithelial tubulogenesis involves complex cell rearrangements that req uire control of both cell adhesion and migration, but the molecular me chanisms regulating these processes during tubule development are not well understood. Interactions of the cytoplasmic protein, beta-catenin , with several molecular partners have been shown to be important for cell signaling and cell-cell adhesion. To examine if beta-catenin has a role in tubulogenesis, we tested the effect of expressing NH2-termin al deleted beta-catenins in an MDCK epithelial cell model for tubuloge nesis. After one day of treatment, hepatocyte growth factor/scatter fa ctor (HGF/SF)-stimulated MDCK cysts initiated tubulogenesis by forming many long cell extensions. Expression of NH2-terminal deleted beta-ca tenins inhibited formation of these cell extensions. Both Delta N90 be ta-catenin, which binds to alpha-catenin, and Delta N131 beta-catenin, which does not bind to alpha-catenin, inhibited formation of cell ext ensions and tubule development, indicating that a function of beta-cat enin distinct from its role in cadherin-mediated cell-cell adhesion is important for tubulogenesis. In cell extensions from parental cysts, adenomatous polyposis coli (APC) protein was localized in linear array s and in punctate clusters at the tips of extensions. Inhibition of ce ll extension formation correlated with the colocalization and accumula tion of NH2-terminal deleted beta-catenin in APC protein clusters and the absence of linear arrays of APC protein. Continued HGF/SF treatmen t of parental cell MDCK cysts resulted in cell proliferation and reorg anization of cell extensions into multicellular tubules. Similar HGF/S F treatment of cysts derived from cells expressing NH2-terminal delete d beta-catenins resulted in cells that proliferated but formed cell ag gregates (polyps) within the cyst rather than tubules. Our results dem onstrate an unexpected role for beta-catenin in cell migration and ind icate that dynamic beta-catenin-APC protein interactions are critical for regulating cell migration during epithelial tubulogenesis.