Protein-kinase-C-mediated β-catenin phosphorylation negatively regulates the Wnt/β-catenin pathway

Normally, the Wnt/β-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/β-catenin pathway is the amino-terminal phosphorylation of β-catenin, marking it for proteasomal degradation. Here we present small-molecule-based identification of protein kinase C (PKC)-mediated β-catenin phosphorylation as a novel mechanism regulating the Wnt/β-catenin pathway. We used a cell-based chemical screen to identify A23187, which inhibits the Wnt/β-catenin pathway. PKC was activated by A23187 treatment and subsequently phosphorylated N-terminal serine (Ser) residues of β-catenin, which promoted β-catenin degradation. Moreover, the depletion of PKCα inhibited the phosphorylation and degradation of β-catenin. Therefore, our findings suggest that the PKC pathway negatively regulates the β-catenin level outside of the Wnt/β-catenin pathway.

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