Journal
ONCOGENE
Volume 31, Issue 23, Pages 2876-2887Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.463
Keywords
prolyl isomerase pin1; orphan receptor TR3; phosphorylation; cell proliferation
Funding
- Ministry of Education, China [B06016]
- Ministry of Science and Technology, China [2007CB914402]
- National Natural Science Foundation of China [30810103905, 30871281, 31000620]
- National Key New Drug Creation Program of China [2009ZX09103-083]
- Fundamental Research Funds for the Central Universities, China [2010121096]
- Science Planning program grant of Fujian Province, China [2009J1010]
- Biomedical Research Council, the Agency for Science, Research and Technology, Singapore [09/1/21/19/604]
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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. Oncogene (2012) 31, 2876-2887; doi:10.1038/onc.2011.463; published online 17 October 2011
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