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-Catenin Interactions with
APC Protein Regulate Epithelial Tubulogenesis
* Department of Anatomy, and Department of Biochemistry and Cardiovascular Research Institute, University of California,
San Francisco, California 94143-0452; and Epithelial tubulogenesis involves complex
cell rearrangements that require control of both cell adhesion and migration, but the molecular mechanisms
regulating these processes during tubule development
are not well understood. Interactions of the cytoplasmic protein, Department of Molecular and Cellular Physiology, Stanford University School of
Medicine, Stanford, California 94305-5426
-catenin, with several molecular partners
have been shown to be important for cell signaling and
cell-cell adhesion. To examine if -catenin has a role in
tubulogenesis, we tested the effect of expressing
NH2-terminal deleted -catenins in an MDCK epithelial cell model for tubulogenesis. After one day of treatment, hepatocyte growth factor/scatter factor (HGF/
SF)-stimulated MDCK cysts initiated tubulogenesis by
forming many long cell extensions. Expression of
NH2-terminal deleted -catenins inhibited formation of
these cell extensions. Both 
N90 -catenin, which
binds to 
-catenin, and N131 -catenin, which does
not bind to -catenin, inhibited formation of cell extensions and tubule development, indicating that a function of -catenin 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 arrays and in punctate clusters at the tips of extensions.
Inhibition of cell extension formation correlated with
the colocalization and accumulation of NH2-terminal
deleted -catenin in APC protein clusters and the absence of linear arrays of APC protein. Continued HGF/
SF treatment of parental cell MDCK cysts resulted in
cell proliferation and reorganization of cell extensions
into multicellular tubules. Similar HGF/SF treatment of
cysts derived from cells expressing NH2-terminal deleted -catenins resulted in cells that proliferated but
formed cell aggregates (polyps) within the cyst rather
than tubules. Our results demonstrate an unexpected
role for -catenin in cell migration and indicate that dynamic -catenin-APC protein interactions are critical
for regulating cell migration during epithelial tubulogenesis.
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