TY - JOUR T1 - Pin1 Competes With APC for β-Catenin JF - Science's STKE JO - Sci. STKE SP - tw321 LP - tw321 DO - 10.1126/stke.2001.99.tw321 VL - 2001 IS - 99 A2 - , Y1 - 2001/09/11 UR - http://stke.sciencemag.org/content/2001/99/tw321.abstract N2 - Pin1 is a peptidyl-prolyl cis-trans isomerase (PPIase) that isomerizes phosphoserine or phosphothreonine residues that are located adjacent to proline residues on proteins, thereby affecting protein catalytic activity or protein-protein interactions. Now, a new function has been identified: Pin1 regulates the turnover of the transcriptional activator β-catenin in cells. Because Pin1 is often overexpressed in cancerous tissue, Ryo et al. used differential display screening to identify genes whose expression is increased by cells overexpressing Pin1 from a plasmid vector. Pin1 increased the expression of several β-catenin-dependent genes. The amount of β-catenin in cells is normally regulated by interactions with the adenomatous polyposis coli protein (APC), which shuttles β-catenin out of the nucleus and targets β-catenin for degradation; APC mutations that prevent the regulation of β-catenin, however, often lead to cancer. The authors found that overexpression of Pin1 led to increased amounts of cellular β-catenin through a mechanism that decreased the turnover of β-catenin. Conversely, in Pin1-deficient mice, amounts of β-catenin were greatly decreased in cells. The binding site of Pin1 on β-catenin was mapped to phosphoSer246, located in a phosphoSer-Pro motif. By binding to this site, Pin1 specifically inhibited APC from binding to β-catenin, suggesting a mechanism by which β-catenin is spared from degradation. Additionally, in the presence of Pin1, β-catenin localizes to the nucleus and presumably transactivates gene expression. Thus, the data suggest a mechanism whereby Pin1 overexpression might lead to increased β-catenin-dependent gene expression resulting in tumorigenesis. A. Ryo, M. Nakamura, G. Wulf, Y.-C. Liou, K. P. Lu, Pin1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC. Nature Cell Biol. 3, 793-801 (2001). [Online Journal] ER -