Protein-kinase-C-mediated beta-catenin phosphorylation negatively regulates the Wnt/beta-catenin pathway.
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.
Gwak
Jungsug
J
PharmcoGenomics Research Center, Inje University, Busan, Korea.
Cho
Munju
M
Gong
Soo-Jung
SJ
Won
Jaejoon
J
Kim
Dong-Eun
DE
Kim
Eun-Young
EY
Lee
Sang Sup
SS
Kim
Mina
M
Kim
Tae Kook
TK
Shin
Jae-Gook
JG
Oh
Sangtaek
S
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*
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