Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity
Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity
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DOI：
10.1038/sj.onc.1210567
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发表时间：
2007-12-06
期刊：
影响因子：
8
通讯作者：
Cao, X.
中科院分区：
文献类型：
--
作者：
Lufei, C.;Koh, T. H.;Cao, X.
信号转导子和转录激活子3（Stat 3）属于对细胞因子信号传导重要的潜在细胞质转录因子家族。Stat 3在各种肿瘤中被组成性激活，并且激活的Stat 3本身也充当癌基因。Stat 3的转录活性受Tyr磷酸化、二聚化和核转位控制。然而，Ser 727上的磷酸化是其最大转录活性所必需的，但其机制尚不清楚。在这里，我们报告肽基脯氨酰顺/反异构酶1（Pin 1），它特异性地识别其靶蛋白上的pSer/Thr-Pro基序，在细胞因子/生长因子刺激后与Stat 3相互作用。Pin 1的过表达促进Stat 3转录活性和靶基因表达，以及转录辅激活因子p300的募集。然而，这些作用在Pin 1缺陷细胞中受到损害，并且完全依赖于Ser 727磷酸化位点。最后，我们发现Pin 1增强了抑瘤素M诱导的乳腺癌细胞中Stat 3介导的上皮间质转化。我们的数据揭示了一种新的，Ser 727磷酸化依赖的，Stat 3的翻译后调节机制。
Signal transducer and activator of transcription 3 (Stat3) belongs to a family of latent cytoplasmic transcription factors important for cytokine signaling. Stat3 is constitutively activated in various tumors, and activated Stat3 itself also acts as an oncogene. Transcriptional activity of Stat3 is controlled by Tyr-phosphorylation, followed by dimerization and nuclear translocation. However, phosphorylation on Ser727 is indispensable for its maximal transcriptional activity with unclear mechanism. Here, we report that peptidyl-prolyl cis/trans isomerase 1 (Pin1), which specifically recognizes the pSer/Thr-Pro motifs on its target proteins, interacts with Stat3 upon cytokine/growth factor stimulation. Overexpression of Pin1 promotes Stat3 transcriptional activity and target gene expression, as well as recruitment of transcription coactivator, p300. These effects, however, were compromised in the Pin1-deficient cells, and were totally dependent on the Ser727 phosphorylation site. Finally, we showed that Pin1 enhances Stat3-mediated epithelial mesenchymal transition in breast cancer cells induced by oncostatin M. Our data reveal a novel, Ser727 phosphorylation-dependent, post-translational regulation mechanism for Stat3.