Active ß-catenin is regulated by the PTEN/PI3 kinase pathway: a role for protein phosphatase PP2A.

ABSTRACT

Dysregulation of Wnt/ß-catenin signaling has been associated with the development and progression of many cancers. The stability and subcellular localization of ß-catenin, a dual functional protein that plays a role in intracellular adhesion and in regulating gene expression, is tightly regulated. However, little is known about the transcriptionally active form of ß-catenin, Active Beta Catenin (ABC), that is unphosphorylated at serine 37 (Ser37) and threonine 41 (Thr41). Elucidating the mechanism by which ß-catenin is activated to generate ABC is vital to the development of therapeutic strategies to block ß-catenin signaling for cancer treatment. Using melanoma, breast and prostate cancer cell lines, we show that while cellular ß-catenin levels are regulated by the Wnt pathway, cellular ABC levels are mainly regulated by the PI3K pathway and are dependent on the phosphatase activity of the protein phosphatase PP2A. Furthermore, we demonstrate that although the PI3K/PTEN pathway does not regulate total ß-catenin protein levels within the cell, it plays a role in regulating the subcellular localization of ß-catenin. Our results support a novel functional interaction/cross-talk between the PTEN/PI3K and Wnt pathways in the regulation of the subcellular/nuclear levels of ABC, which is crucially important for the protein's activity as a transcription factor and its biological effects in health and disease.