Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation
Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation
复制标题
DOI：
10.1126/science.1137065
复制
发表时间：
2007-06-15
期刊：
影响因子：
56.9
通讯作者：
Niehrs, Christof
中科院分区：
文献类型：
--
作者：
Bilic, Josipa;Huang, Ya-Lin;Niehrs, Christof
多种信号通路，包括Wnt信号通路，参与动物发育，干细胞生物学和人类癌症。虽然Wnt通路的许多组分已经被鉴定，但Wnt与其受体Frizzled和低密度脂蛋白受体相关蛋白6（LRP 6）结合触发下游信号传导事件的机制仍存在未解决的问题。通过脊椎动物细胞的实时成像，我们表明Wnt处理快速诱导质膜相关的LRP 6聚集体。LRP 6聚集体被磷酸化，并且可以作为核糖体大小的多蛋白复合物被洗涤剂溶解。磷酸-LRP 6聚集体含有Wnt途径组分，但除了小窝蛋白之外没有常见的囊泡交通标志物。支架蛋白Dishevelled（Dvl）是LRP 6磷酸化和聚集所需的。我们提出Wnt诱导受体和Dvl在LRP 6信号体中的共聚集，这反过来触发LRP 6磷酸化以促进Axin募集和β-连环蛋白稳定。
Multiple signaling pathways, including Wnt signaling, participate in animal development, stem cell biology, and human cancer. Although many components of the Wnt pathway have been identified, unresolved questions remain as to the mechanism by which Wnt binding to its receptors Frizzled and Low-density lipoprotein receptor-related protein 6 (LRP6) triggers downstream signaling events. With live imaging of vertebrate cells, we show that Wnt treatment quickly induces plasma membrane-associated LRP6 aggregates. LRP6 aggregates are phosphorylated and can be detergent-solubilized as ribosome-sized multiprotein complexes. Phospho-LRP6 aggregates contain Wnt-pathway components but no common vesicular traffic markers except caveolin. The scaffold protein Dishevelled (Dvl) is required for LRP6 phosphorylation and aggregation. We propose that Wnts induce coclustering of receptors and Dvl in LRP6-signalosomes, which in turn triggers LRP6 phosphorylation to promote Axin recruitment and beta-catenin stabilization.