Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis
Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis
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脯氨酰异构酶 Pin1 稳定并激活孤儿核受体 TR3 以促进有丝分裂
DOI：
10.1038/onc.2011.463
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发表时间：
2012-06-01
期刊：
影响因子：
8
通讯作者：
Wu, Q.
中科院分区：
文献类型：
--
作者：
Chen, H-Z;Li, L.;Wu, Q.
Pin1通过“后磷酸化”机制使磷酸化- ser /Thr-Pro基序异构化，从而调节磷酸化蛋白的一个子集。在这里，我们将TR3描述为一种新的Pin1底物，TR3的有丝分裂功能依赖于Pin1诱导的异构化。TR3上至少有三个磷酸化ser - pro基序与Pin1结合。TR3的Ser95-Pro基序是Pin1通过延缓TR3降解来增强其稳定性的关键位点。Pin1还可以通过phospho-Ser431-Pro基序催化TR3，该基序被细胞外信号调节激酶2 （ERK2）磷酸化，从而增强TR3的转激活。此外，Pin1不仅促进TR3靶向TR3新的下游靶标cyclin D2的启动子，还促进TR3募集p300，从而诱导细胞增殖。重要的是，我们发现TR3在体外和体内促进肿瘤生长都离不开Pin1。因此，我们的研究表明Pin1通过异构化TR3在细胞增殖中起重要作用。中华肿瘤杂志，2012,31,2876-2887；doi: 10.1038 / onc.2011.463;2011年10月17日在线发布
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