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Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC.

Nature cell biology | Sep 4, 2001

http://www.ncbi.nlm.nih.gov/pubmed/11533658

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

Pubmed ID: 11533658 RIS Download

Mesh terms: Adenomatous Polyposis Coli | Amino Acid Sequence | Amino Acid Substitution | Cadherins | Cell Nucleus | Cytoskeletal Proteins | Gene Expression Regulation | Genes, Reporter | HeLa Cells | Humans | Kinetics | Mutagenesis, Site-Directed | Peptidylprolyl Isomerase | Phosphorylation | Phosphothreonine | Protein Transport | Recombinant Fusion Proteins | Recombinant Proteins | Trans-Activators | Transfection | beta Catenin

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