TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis.
TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis.
复制标题
转化生长因子-β诱导的DACT1生物分子凝聚体抑制Wnt信号，促进骨转移。
DOI：
10.1038/s41556-021-00641-w
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发表时间：
2021-03
影响因子：
21.3
通讯作者：
Kang Y
中科院分区：
文献类型：
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作者：
Esposito M;Fang C;Cook KC;Park N;Wei Y;Spadazzi C;Bracha D;Gunaratna RT;Laevsky G;DeCoste CJ;Slabodkin H;Brangwynne CP;Cristea IM;Kang Y
细胞内信号传导的复杂性既需要分子参与者的多样性，也需要将活性隔离到细胞内的独特隔室。最近的研究发现，液-液相分离的作用提供了一个独特的机制，空间分离的蛋白质调节信号通路串扰。在这里，我们发现DACT 1被TGF-β诱导，并在细胞质中形成蛋白质凝聚物以抑制Wnt信号传导。这些浓缩物不定位于任何已知的细胞器，而是作为相分离的蛋白质细胞质体存在。DACT 1蛋白内固有无序结构域的缺失消除了其形成蛋白质缩合物和抑制Wnt信号传导的能力。这些颗粒的分离和质谱分析揭示了螯合酪蛋白激酶2（Wnt途径激活剂）的蛋白质机制的复合物。我们进一步证明，DACT 1凝聚物在体内维持，DACT 1是乳腺癌和前列腺癌骨转移的关键。
The complexity of intracellular signaling requires both a diversity of molecular players and the sequestration of activity to unique compartments within the cell. Recent findings on the role of liquid-liquid phase separation provide a distinct mechanism for spatial segregation of proteins to regulate signaling pathway crosstalk. Here we discover that DACT1 is induced by TGF-β and forms protein condensates in the cytoplasm to repress Wnt signaling. These condensates do not localize to any known organelles but rather exist as phase-separated proteinaceous cytoplasmic bodies. Deletion of intrinsically disordered domains within the DACT1 protein eliminates its ability to both form protein condensates and suppress Wnt signaling. Isolation and mass spectrometry analysis of these particles revealed a complex of protein machinery that sequesters Casein Kinase 2, a Wnt pathway activator. We further demonstrate that DACT1 condensates are maintained in vivo and that DACT1 is critical to breast and prostate cancer bone metastasis.