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Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

Oncogene volume 31, pages 2876–2887 (2012)Cite this article

Abstract

Pin1 regulates a subset of phosphoproteins by isomerizing phospho-Ser/Thr-Pro motifs via a ‘post-phosphorylation’ mechanism. Here, we characterize TR3 as a novel Pin1 substrate, and the mitogenic function of TR3 depends on Pin1-induced isomerization. There are at least three phospho-Ser-Pro motifs on TR3 that bind to Pin1. The Ser95-Pro motif of TR3 is the key site through which Pin1 enhances TR3 stability by retarding its degradation. Pin1 can also catalyze TR3 through phospho-Ser431-Pro motif, which is phosphorylated by extracellular signal-regulated kinase 2 (ERK2), resulting in enhanced TR3 transactivation. Furthermore, Pin1 not only facilitates TR3 targeting to the promoter of cyclin D2, a novel downstream target of TR3, but also promotes TR3 to recruit p300, thereby inducing cell proliferation. Importantly, we found that Pin1 is indispensable for TR3 to promote tumor growth both in vitro and in vivo. Our study thus suggests that Pin1 has an important role in cell proliferation by isomerizing TR3.

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Acknowledgements

This work was supported by grants from Ministry of Education, China (Project 111, B06016) to WQ and YCL; grants from the Ministry of Science and Technology, China (2007CB914402) to WQ; the National Natural Science Foundation of China (30810103905 and 30871281 to WQ, 31000620 to CHZ); grants from the National Key New Drug Creation Program of China (2009ZX09103-083) to WQ; grants from the Fundamental Research Funds for the Central Universities, China (2010121096) to CHZ; Science Planning program grant of Fujian Province, China (2009J1010); and the grant (09/1/21/19/604) from the Biomedical Research Council, the Agency for Science, Research and Technology, Singapore to YCL.

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Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, PR China

    H-Z Chen, L Li, W-J Wang, X-D Du, Q Wen, J-P He, B-X Zhao, G-D Li & Q Wu

  2. Department of Biological Sciences, National University of Singapore, Singapore, Republic of Singapore

    W Zhou, Y Xia, Q-Y Yang, C-L Hew & Y-C Liou

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  1. H-Z Chen
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Correspondence to Y-C Liou or Q Wu.

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Chen, HZ., Li, L., Wang, WJ. et al. Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis. Oncogene 31, 2876–2887 (2012). https://doi.org/10.1038/onc.2011.463

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