Background

The Wnt family includes several secreted glycoproteins that play important roles in animal development. Aberrant activation of Wnt signaling pathways is involved in several types of cancers. Wnt members bind to the Frizzled family of proteins and activate several signaling pathways. The canonical Wnt/β-catenin pathway requires a coreceptor from proteins belonging to the low-density lipoprotein receptor family, such as LRP5 and LRP6. Upon stimulation with Wnt, LRP6 is phosphorylated by kinases such as GSK-3 and CK1 and subsequently recruits Axin to the membrane. In the absence of Wnt stimulation, the multidomain scaffold proteins Axin1 and Axin2 negatively regulate Wnt signaling. Axin1 complexes with APC, GSK-3β, Dvl and β-catenin and promotes the GSK-3β-mediated phosphorylation and subsequent degradation of β-catenin. The Disheveled proteins inhibit glycogen synthase kinase-3β, thereby promoting β-catenin stabilization. Naked inhibits the canonical Wnt/β-catenin pathway by binding to Dsh proteins and directing Dsh activity towards the planar cell polarity pathway.

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