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© The Rockefeller University Press, 0021-9525/1997//1651 $5.00
The Journal of Cell Biology, Volume 137, Number 7, , 1997 1651-1662

Article

Dynamics of β-Catenin Interactions with APC Protein Regulate Epithelial Tubulogenesis



Anne L. Pollack*, Angela I.M. Barth{ddagger}, Yoram Altschuler*, W. James Nelson{ddagger}, and Keith E. Mostov*

* Department of Anatomy, and Department of Biochemistry and Cardiovascular Research Institute, University of California, San Francisco, California 94143-0452; and {ddagger} Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305-5426

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, β-catenin, with several molecular partners have been shown to be important for cell signaling and cell–cell adhesion. To examine if β-catenin has a role in tubulogenesis, we tested the effect of expressing NH2-terminal deleted β-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 β-catenins inhibited formation of these cell extensions. Both {Delta}N90 β-catenin, which binds to {alpha}-catenin, and {Delta}N131 β-catenin, which does not bind to {alpha}-catenin, inhibited formation of cell extensions and tubule development, indicating that a function of β-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 β-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 β-catenins resulted in cells that proliferated but formed cell aggregates (polyps) within the cyst rather than tubules. Our results demonstrate an unexpected role for β-catenin in cell migration and indicate that dynamic β-catenin–APC protein interactions are critical for regulating cell migration during epithelial tubulogenesis.

Abbreviations used in this paper: APC, adenomatous polyposis coli; β-cat*, full length β-catenin; Dox, doxycycline; HGF/SF, hepatocyte growth factor/scatter factor; Lu, luciferase; ppI, propidium iodide.

A.L. Pollack and A.I.M. Barth contributed equally to this paper.

Please address all correspondence to Angela I.M. Barth, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5426; Tel.: (415) 725-7596; Fax: (415) 725-8021; E-mail: angelab{at}leland.stanford.edu

A.L. Pollack's present address is Department of Cell Biology and Anatomy, University of Arizona, 1501 North Campbell Road, Tucson, AZ 85724.


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