Pygopus and Legless target Armadillo/β-catenin to the nucleus to enable its transcriptional co-activator function
Pygopus and Legless target Armadillo/β-catenin to the nucleus to enable its transcriptional co-activator function
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DOI：
10.1038/ncb1141
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发表时间：
2004-07-01
影响因子：
21.3
通讯作者：
Bienz, M
中科院分区：
文献类型：
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作者：
Townsley, FM;Cliffe, A;Bienz, M
WNT信号控制在正常和恶性发育过程中起作用的基因的转录(1，2)。经典的Wnt配体的刺激通过阻止β-连环蛋白的磷酸化激活β-连环蛋白(或果蝇黑腹果蝇Armadillo)，导致其稳定和移位到细胞核。在这里，Armadillo/β-catenin与TCF/Lef转录因子结合，并招募染色质修饰和重塑复合体来转录Wnt靶基因(3-6)。Armadillo/β-catenin的转录活性依赖于最近在果蝇中发现的两种保守的核蛋白：Pygopus(PYGO)和Legless/bcl9(Lgs)(7-10)。LGS作为PYGO和Armadillo/β-catenin(7)之间的接头，但Armadillo/β-catenin是如何被PYGO和LGS控制的还不清楚。在这里，我们证明了LGS的核定位完全依赖于PYGO，而PYGO本身是结构性地定位于核；因此，PYGO起着核锚的作用。在无翼信号传递过程中，PYGO也是高水平核Armadillo所必需的，与LGS一起增加APC突变癌细胞中β-连环蛋白的转录活性。值得注意的是，将Armadillo与核定位序列联系起来可以挽救PYGO和lgs突变的苍蝇胚胎。这表明PYGO和LGS在靶向Armadillo/β-catenin到细胞核中发挥作用，从而确保其在Wnt信号转导过程中对TCF的可用性。
Wnt signalling controls the transcription of genes that function during normal and malignant development(1,2). Stimulation by canonical Wnt ligands activates beta-catenin (or Drosophila melanogaster Armadillo) by blocking its phosphorylation, resulting in its stabilization and translocation to the nucleus. Here, Armadillo/beta-catenin binds to TCF/LEF transcription factors and recruits chromatin-modifying and -remodelling complexes to transcribe Wnt target genes(3-6). The transcriptional activity of Armadillo/beta-catenin depends on two conserved nuclear proteins recently discovered in Drosophila, Pygopus (Pygo) and Legless/BCL-9 (Lgs)(7-10). Lgs functions as an adaptor between Pygo and Armadillo/beta-catenin(7), but how Armadillo/beta-catenin is controlled by Pygo and Lgs is not known. Here, we show that the nuclear localization of Lgs entirely depends on Pygo, which itself is constitutively localized to the nucleus; thus, Pygo functions as a nuclear anchor. Pygo is also required for high nuclear Armadillo levels during Wingless signalling, and together with Lgs increases the transcriptional activity of beta-catenin in APC mutant cancer cells. Notably, linking Armadillo to a nuclear localization sequence rescues pygo and lgs mutant fly embryos. This indicates that Pygo and Lgs function in targeting Armadillo/beta-catenin to the nucleus, thus ensuring its availability to TCF during Wnt signalling.