Subcellular localization and signaling properties of dishevelled in developing vertebrate embryos
Subcellular localization and signaling properties of dishevelled in developing vertebrate embryos
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DOI：
10.1016/j.cub.2005.04.062
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发表时间：
2005-06-07
期刊：
影响因子：
9.2
通讯作者：
Wallingford, JB
中科院分区：
文献类型：
--
作者：
Park, TJ;Gray, RS;Wallingford, JB
Dishevelled蛋白介导几种不同的生物过程。有趣的是，在爪蟾Dishevelled（Xdsh）通过经典Wnt信号传导控制细胞命运的相同组织中，它也通过脊椎动物平面细胞极性（PCP）级联控制细胞极性[1-9]。Dishevelled的亚细胞定位与其信号传导活性之间的关系尚不清楚;根据所检查的生物体和细胞类型，已报告了相互矛盾的结果[8-20]。我们已经通过开发新的试剂来处理这个问题，以将野生型Dishevelled蛋白隔离在细胞膜处或远离细胞膜。从细胞膜去除Dishevelled通过阻止Rho/Rac激活和中外侧细胞极化来破坏会聚延伸。通过操纵K -> M（dsh（1））的亚细胞定位，我们表明该突变抑制Rac的Dishevelled激活，而不管其亚细胞定位如何。这些数据表明，Dishevelled的膜定位是脊椎动物PCP信号传导的先决条件。然而，膜靶向和细胞质靶向的Dishevelled都可以有效地激活经典Wnt信号传导，这表明Dishevelled蛋白的局部浓度，而不是其空间定位，是经典Wnt信号传导的核心。这些结果表明，在脊椎动物胚胎中，亚细胞定位不足以解释Dishevelled在经典Wnt与PCP信号级联中的通路特异性。
The Dishevelled protein mediates several diverse biological processes. Intriguingly, within the same tissues where Xenopus Dishevelled (Xdsh) controls cell fate via canonical Wnt signaling, it also controls cell polarity via the vertebrate planar cell polarity (PCP) cascade [1-9]. The relationship between subcellular localization of Dishevelled and its signaling activities remains unclear; conflicting results have been reported depending upon the organism and cell types examined [8-20]. We have approached this issue by developing new reagents to sequester wild-type Dishevelled protein either at the cell membrane or away from the cell membrane. Removal of Dishevelled from the cell membrane disrupts convergent extension by preventing Rho/Rac activation and mediolateral cell polarization. By manipulating the subcellular localization of K -> M (dsh(1)), we show that this mutation inhibits Dishevelled activation of Rac, regardless of its subcellular localization. These data demonstrate that membrane localization of Dishevelled is a prerequisite for vertebrate PCP signaling. However, both membrane-targeted and cytoplasm-targeted Dishevelled can potently activate canonical Wnt signaling, suggesting that local concentration of Dishevelled protein, but not its spatial localization, is central to canonical Wnt signaling. These results suggest that in vertebrate embryos, subcellular localization is insufficient to account for the pathway specificity of Dishevelled in the canonical Wnt versus PCP signaling cascades.