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.
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Acknowledgements
We thank M. Yamamoto for providing reagents for the initial differential display screen; X. He for discussions; T. Hunter for Pin1 knockout mice; I. Kosugi for technical instructions; B. Vogelstein, X. He, R. Pestell and S. Hatakeyama for reagents; and X. Zhou, O. Kops and P. J. Lu in the Lu laboratory for their important contributions. A.R., G.W., Y.-C.L. and N.M. are fellows of the Japan Society for the Promotion of Science, the DOD Breast Cancer Research Program, the National Sciences and Engineering Research Council of Canada and the Human Frontier Research Program, respectively. K.P.L. is a Pew Scholar and a Leukemia and Lymphoma Society Scholar. This study was supported the NIH grants to K.P.L.
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Figure S1
β-Catenin structure and its binding sites for APC and Pin1. (PDF 118 kb)
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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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DOI: https://doi.org/10.1038/ncb0901-793
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