Yamamoto Hideki, Komekado Hideyuki, Kikuchi Akira
Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
Dev Cell. 2006 Aug;11(2):213-23. doi: 10.1016/j.devcel.2006.07.003.
beta-catenin-mediated Wnt signaling is critical in animal development and tumor progression. The single-span transmembrane Wnt receptor, low-density lipoprotein receptor-related protein 6 (LRP6), interacts with Axin to promote the Wnt-dependent accumulation of beta-catenin. However, the molecular mechanism of receptor internalization and its impact on signaling are unclear. Here, we present evidence that LRP6 is internalized with caveolin and that the components of this endocytic pathway are required not only for Wnt-3a-induced internalization of LRP6 but also for accumulation of beta-catenin. Overall, our data suggest that Wnt-3a triggers the interaction of LRP6 with caveolin and promotes recruitment of Axin to LRP6 phosphorylated by glycogen synthase kinase-3beta and that caveolin thereby inhibits the binding of beta-catenin to Axin. Thus, caveolin plays critical roles in inducing the internalization of LRP6 and activating the Wnt/beta-catenin pathway. We also discuss the idea that distinct endocytic pathways correlate with the specificity of Wnt signaling events.
β-连环蛋白介导的Wnt信号传导在动物发育和肿瘤进展中至关重要。单跨膜Wnt受体低密度脂蛋白受体相关蛋白6（LRP6）与Axin相互作用，促进β-连环蛋白的Wnt依赖性积累。然而，受体内化的分子机制及其对信号传导的影响尚不清楚。在这里，我们提供证据表明LRP6与小窝蛋白一起内化，并且这种内吞途径的组分不仅是Wnt-3a诱导的LRP6内化所必需的，也是β-连环蛋白积累所必需的。总体而言，我们的数据表明Wnt-3a触发LRP6与小窝蛋白的相互作用，并促进Axin募集到由糖原合酶激酶-3β磷酸化的LRP6上，并且小窝蛋白由此抑制β-连环蛋白与Axin的结合。因此，小窝蛋白在诱导LRP6内化和激活Wnt/β-连环蛋白途径中起关键作用。我们还讨论了不同内吞途径与Wnt信号事件特异性相关的观点。
