The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility
The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility
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DOI：
10.1038/ncomms1861
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发表时间：
2012-05-01
影响因子：
16.6
通讯作者：
Takahashi, Masahide
中科院分区：
文献类型：
--
作者：
Ishida-Takagishi, Maki;Enomoto, Atsushi;Takahashi, Masahide
Disheveled 是经典和非经典 Wnt 信号通路的常见介质，对胚胎发育、组织维持和癌症进展非常重要。在非经典 Wnt 信号通路中，作用于 Disheveled 下游的小 GTP 酶 Rho 家族在细胞迁移中发挥重要作用。非经典 Wnt 信号通路调节 Rac 激活的机制仍不清楚。在这里，我们证明 Daple（具有高频率亮氨酸残基的 Dishevelled 相关蛋白）通过与 Dishevelled 相互作用调节 Wnt5a 介导的 Rac 激活和板状伪足的形成。 Daple 增加了 Disheveled 与非典型蛋白激酶 C 亚型的关联，从而促进 Rac 激活。因此，Daple 缺陷会损害体内伤口愈合过程中成纤维细胞和上皮细胞的迁移。这些发现表明 Daple 与 Dishevelled 相互作用以指导 Dishevelled/蛋白激酶。蛋白复合物激活 Rac，进而介导细胞迁移所需的非经典 Wnt 信号通路。
Dishevelled is the common mediator of canonical and non-canonical Wnt signalling pathways, which are important for embryonic development, tissue maintenance and cancer progression. In the non-canonical Wnt signalling pathway, the Rho family of small GTPases acting downstream of Dishevelled has essential roles in cell migration. The mechanisms by which the non-canonical Wnt signalling pathway regulates Rac activation remain unknown. Here we show that Daple (Dishevelled-associating protein with a high frequency of leucine residues) regulates Wnt5a-mediated activation of Rac and formation of lamellipodia through interaction with Dishevelled. Daple increases the association of Dishevelled with an isoform of atypical protein kinase C, consequently promoting Rac activation. Accordingly, Daple deficiency impairs migration of fibroblasts and epithelial cells during wound healing in vivo. These findings indicate that Daple interacts with Dishevelled to direct the Dishevelled/protein kinase. protein complex to activate Rac, which in turn mediates the non-canonical Wnt signalling pathway required for cell migration.