Pin1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with

Abstract

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 β-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 β-catenin target genes, including those encoding cyclin D1 and c-Myc. Manipulation of Pin1 levels affects the stability of β-catenin in vitro. Furthermore, β-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 β-catenin, inhibits its interaction with APC and increases its translocation into the nucleus. Thus, Pin1 is a novel regulator of β-catenin signalling and its overexpression might contribute to the upregulation of β-catenin in tumours such as breast cancer, in which APC or β-catenin mutations are not common.

Cite this article

Ryo, A., Nakamura, M., Wulf, G. et al. Pin1 regulates turnover and subcellular localization of β-catenin by inhibiting its interaction with APC. Nat Cell Biol 3, 793–801 (2001). https://doi.org/10.1038/ncb0901-793

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