
<ArticleTitle><prot>Pin1</prot> regulates turnover and subcellular localization of <prot>beta-catenin</prot> by inhibiting its interaction with <prot>APC</prot>.</ArticleTitle>
<AbstractText>Phosphorylation on a serine or threonine residue preceding proline (Ser/Thr-Pro) is a key regulatory mechanism, and the conformation of certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by the <prot>prolyl isomerase</prot> <prot>Pin1</prot>. Whereas the inhibition of <prot>Pin1</prot> induces apoptosis, <prot>Pin1</prot> is strikingly overexpressed in a subset of human tumours. Here we show that <prot>Pin1</prot> regulates <prot>beta-catenin</prot> turnover and subcellular localization by interfering with its interaction with <prot>adenomatous polyposis coli protein</prot> (<prot>APC</prot>). A differential-display screen reveals that <prot>Pin1</prot> increases the transcription of several <prot>beta-catenin</prot> target genes, including those encoding <prot>cyclin D1</prot> and <prot>c-Myc</prot>. Manipulation of <prot>Pin1</prot> levels affects the stability of <prot>beta-catenin</prot> in vitro. Furthermore, <prot>beta-catenin</prot> levels are decreased in <prot>Pin1</prot>-deficient mice but are increased and correlated with <prot>Pin1</prot> overexpression in human breast cancer. <prot>Pin1</prot> directly binds a phosphorylated Ser-Pro motif next to the <prot>APC</prot>-binding site in <prot>beta-catenin</prot>, inhibits its interaction with <prot>APC</prot> and increases its translocation into the nucleus. Thus, <prot>Pin1</prot> is a novel regulator of <prot>beta-catenin</prot> signalling and its overexpression might contribute to the upregulation of <prot>beta-catenin</prot> in tumours such as breast cancer, in which <prot>APC</prot> or <prot>beta-catenin</prot> mutations are not common.</AbstractText>
