Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.
Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.
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DOI：
10.1083/jcb.200806172
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发表时间：
2008-10-06
期刊：
影响因子：
--
通讯作者：
Kao HY
中科院分区：
文献类型：
--
作者：
Stanya KJ;Liu Y;Means AR;Kao HY
视黄酸和甲状腺激素受体（SMRT）沉默介质是一种参与多种信号通路和人类疾病的转录辅抑制因子。然而，SMRT稳定性的监管在很大程度上仍未得到探索。我们发现肽基脯氨酸异构酶Pin1在体外和哺乳动物细胞中与SMRT相互作用。这种相互作用需要Pin1的WW结构域和SMRT的磷酸化。Pin1调节SMRT蛋白的稳定性，从而影响SMRT依赖性的转录抑制。Pin1相互作用需要SMRT在多个位点磷酸化，而这些位点可以被Cdk2磷酸化，而Cdk2与SMRT相互作用。cdk2介导的SMRT磷酸化是Pin1结合所必需的，会降低SMRT的稳定性，而这些磷酸化位点的突变会消除Pin1的结合并稳定SMRT。最后，SMRT稳定性的降低发生在Her2/Neu/ErbB2激活的反应中，该受体在调节SMRT稳定性和细胞对他莫昔芬反应的信号级联中在Pin1和Cdk2的上游起作用。
Silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) is a transcriptional corepressor that participates in diverse signaling pathways and human diseases. However, regulation of SMRT stability remains largely unexplored. We show that the peptidyl-prolyl isomerase Pin1 interacts with SMRT both in vitro and in mammalian cells. This interaction requires the WW domain of Pin1 and SMRT phosphorylation. Pin1 regulates SMRT protein stability, thereby affecting SMRT-dependent transcriptional repression. SMRT phosphorylation at multiple sites is required for Pin1 interaction, and these sites can be phosphorylated by Cdk2, which interacts with SMRT. Cdk2-mediated phosphorylation of SMRT is required for Pin1 binding and decreases SMRT stability, whereas mutation of these phosphorylation sites abrogates Pin1 binding and stabilizes SMRT. Finally, decreases in SMRT stability occur in response to the activation of Her2/Neu/ErbB2, and this receptor functions upstream of both Pin1 and Cdk2 in the signaling cascade that regulates SMRT stability and cellular response to tamoxifen.
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