Journal
JOURNAL OF CELL SCIENCE
Volume 119, Issue 22, Pages 4702-4709Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.03256
Keywords
Wnt/beta-catenin pathway; protein kinase C; phosphorylation; degradation
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Normally, the Wnt/beta-catenin pathway controls developmental processes and homeostasis, but abnormal activation of this pathway is a frequent event during the development of cancer. The key mechanism in regulation of the Wnt/beta-catenin pathway is the amino-terminal phosphorylation of beta-catenin, marking it for proteasomal degradation. Here we present small-molecule-based identification of protein kinase C (PKC)-mediated beta-catenin phosphorylation as a novel mechanism regulating the Wnt/beta-catenin pathway. We used a cell- based chemical screen to identify A23187, which inhibits the Wnt/beta-catenin pathway. PKC was activated by A23187 treatment and subsequently phosphorylated N-terminal serine (Ser) residues of beta-catenin, which promoted beta-catenin degradation. Moreover, the depletion of PKC inhibited the phosphorylation and degradation of beta-catenin. Therefore, our findings suggest that the PKC pathway negatively regulates the -catenin level outside of the Wnt/beta-catenin pathway.
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