Wnt signaling plays a critical role in development across species and is dysregulated in a host of human diseases. A key step in signal transduction is the formation of Wnt receptor signalosomes, during which a large number of components translocate to the membrane, cluster together and amplify downstream signaling. However, the molecular processes that coordinate these events remain poorly defined. Here, we show that Daam2 regulates canonical Wnt signaling via the PIP₂–PIP5K axis through its association with Rac1. Clustering of Daam2-mediated Wnt receptor complexes requires both Rac1 and PIP5K, and PIP5K promotes membrane localization of these complexes in a Rac1-dependent manner. Importantly, the localization of Daam2 complexes and Daam2-mediated canonical Wnt signaling is dependent upon actin polymerization. These studies – in chick spinal cord and human and monkey cell lines – highlight novel roles for Rac1 and the actin cytoskeleton in the regulation of canonical Wnt signaling and define Daam2 as a key scaffolding hub that coordinates membrane translocation and signalosome clustering.

Wnt 信号传导在跨物种的发育中起关键作用，并且在许多人类疾病中失调。信号转导的一个关键步骤是 Wnt 受体信号体的形成，在此期间，大量成分转移到膜上，聚集在一起并放大下游信号。然而，协调这些事件的分子过程仍然不清楚。在这里，我们表明 Daam2 通过 PIP _{2调节规范 Wnt 信号}-PIP5K 轴通过其与 Rac1 的关联。Daam2 介导的 Wnt 受体复合物的聚集需要 Rac1 和 PIP5K，而 PIP5K 以 Rac1 依赖性方式促进这些复合物的膜定位。重要的是，Daam2 复合物和 Daam2 介导的经典 Wnt 信号的定位取决于肌动蛋白聚合。这些研究——在鸡脊髓和人和猴细胞系中——强调了 Rac1 和肌动蛋白细胞骨架在调节经典 Wnt 信号传导中的新作用，并将 Daam2 定义为协调膜易位和信号体聚集的关键支架中枢。