title: Protein-kinase-C-mediated beta-catenin phosphorylation negatively regulates the Wnt/beta-catenin pathway.
abstract: 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 PKCalpha inhibited the phosphorylation and degradation of beta-catenin. Therefore, our findings suggest that the PKC pathway negatively regulates the beta-catenin level outside of the Wnt/beta-catenin pathway.
authors.affiliation: PharmcoGenomics Research Center, Inje University, Busan, Korea.
authors.forename: Jungsug
authors.initials: J
authors.lastname: Gwak
authors.forename: Munju
authors.initials: M
authors.lastname: Cho
authors.forename: Soo-Jung
authors.initials: SJ
authors.lastname: Gong
authors.forename: Jaejoon
authors.initials: J
authors.lastname: Won
authors.forename: Dong-Eun
authors.initials: DE
authors.lastname: Kim
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Sang Sup
authors.initials: SS
authors.lastname: Lee
authors.forename: Mina
authors.initials: M
authors.lastname: Kim
authors.forename: Tae Kook
authors.initials: TK
authors.lastname: Kim
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D007476:Ionophores; D051153:Wnt Proteins; D051176:beta Catenin; D000001:Calcimycin; D000071679:Glycogen Synthase Kinase 3 beta; D051571:Protein Kinase C-alpha; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; D002118:Calcium