Identification of PCTA, a TGIF antagonist that promotes PML function in TGF-β signalling
Identification of PCTA, a TGIF antagonist that promotes PML function in TGF-β signalling
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DOI：
10.1038/emboj.2008.109
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发表时间：
2008-07-09
期刊：
影响因子：
11.4
通讯作者：
Atfi, Azeddine
中科院分区：
文献类型：
--
作者：
Faresse, Nourdine;Colland, Frederic;Atfi, Azeddine
TGIF同源结构域蛋白在TGF-β信号传导途径中作为重要的负调节剂发挥作用。TGIF的抑制功能部分地通过其将肿瘤抑制细胞质早幼粒细胞白血病（cPML）隔离在细胞核中的能力来执行，从而防止Smad 2被活化的TGF-β I型受体磷酸化。在这里，我们报告的识别PCTA（PML竞争TGIF协会），TGIF拮抗剂，促进TGF-β诱导的转录和细胞抑制反应。我们提供的证据表明，PCTA的功能，TGF-β信号通过缓解抑制Smad 2磷酸化的TGF-β。此外，我们证明PCTA选择性地与cPML竞争TGIF关联，导致cPML在细胞质中积累，在那里它与SARA关联并协调Smad 2通过活化的TGF-β I型受体磷酸化的通路。因此，我们对PCTA作用模式的研究结果为TGF-β信号网络中TGIF和cPML之间拮抗性相互作用的分子机制提供了新的重要见解。
The TGIF homoeodomain protein functions as an important negative regulator in the TGF-beta signalling pathway. The inhibitory function of TGIF is executed in part through its ability to sequester the tumour suppressor cytoplasmic promyelocytic leukaemia (cPML) in the nucleus, thereby preventing the phosphorylation of Smad2 by the activated TGF-beta type I receptor. Here, we report on the identification of PCTA (PML competitor for TGIF association), a TGIF antagonist that promotes TGF-beta-induced transcriptional and cytostatic responses. We provide evidence that PCTA functions in TGF-beta signalling by relieving the suppression of Smad2 phosphorylation by TGIF. Furthermore, we demonstrate that PCTA selectively competes with cPML for TGIF association, resulting in the accumulation of cPML in the cytoplasm, where it associates with SARA and coordinates the access of Smad2 for phosphorylation by the activated TGF-beta type I receptor. Thus, our findings on the mode of action of PCTA provide new and important insights into the molecular mechanism underlying the antagonistic interplay between TGIF and cPML in the TGF-beta signalling network.