The DIX domain targets dishevelled to actin stress fibres and vesicular membranes
The DIX domain targets dishevelled to actin stress fibres and vesicular membranes
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DOI：
10.1038/nature01056
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发表时间：
2002-10-17
期刊：
影响因子：
64.8
通讯作者：
Overduin, M
中科院分区：
文献类型：
--
作者：
Capelluto, DGS;Kutateladze, TG;Overduin, M
结直肠癌是由调节β-连环蛋白水平的Wnt通路组分突变引起的（1）。Dishevelled（Dvl或Dsh）在Wnt受体下游发出信号，并在细胞增殖（1）和胚胎轴形成（2）期间稳定β-连环蛋白。此外，Dvl有助于原肠胚形成期间的细胞骨架重组（3-5）和不对称细胞分裂期间的有丝分裂纺锤体定向（6）。Dvl属于真核细胞信号蛋白家族，其包含结构和生物学功能未知的保守的85个残基模块，称为DIX结构域（7）。在这里，我们表明，DIX域介导靶向肌动蛋白应力纤维和细胞质囊泡在体内。通过核磁共振光谱（NMR）确定两个螺旋之间的肌动蛋白和磷脂的相邻相互作用位点。肌动蛋白结合基序的突变消除了Dvl的细胞骨架定位，但增强了爪蟾Wnt/β-连环蛋白信号传导和轴诱导。相比之下，磷脂相互作用位点的突变破坏Dvl、Dvl磷酸化和Wnt/β-连环蛋白途径活化的囊泡缔合。我们建议，分区Dvl成细胞骨架和囊泡池的DIX结构域代表一个点的分歧Wnt信号。
Colorectal cancer results from mutations in components of the Wnt pathway that regulate beta-catenin levels(1). Dishevelled (Dvl or Dsh) signals downstream of Wnt receptors and stabilizes beta-catenin during cell proliferation(1) and embryonic axis formation(2). Moreover, Dvl contributes to cytoskeletal reorganization during gastrulation(3-5) and mitotic spindle orientation during asymmetric cell division(6). Dvl belongs to a family of eukaryotic signalling proteins that contain a conserved 85-residue module of unknown structure and biological function called the DIX domain(7). Here we show that the DIX domain mediates targeting to actin stress fibres and cytoplasmic vesicles in vivo. Neighbouring interaction sites for actin and phospholipid are identified between two helices by nuclear magnetic resonance spectroscopy (NMR). Mutation of the actin-binding motif abolishes the cytoskeletal localization of Dvl, but enhances Wnt/beta-catenin signalling and axis induction in Xenopus. By contrast, mutation of the phospholipid interaction site disrupts vesicular association of Dvl, Dvl phosphorylation, and Wnt/beta-catenin pathway activation. We propose that partitioning of Dvl into cytoskeletal and vesicular pools by the DIX domain represents a point of divergence in Wnt signalling.