FIGURE 6.

Proposed model of c-Cbl in regulating β-catenin in Wnt signaling. In Wnt-off phase, cytosolic phosphorylated β-catenin is targeted by E3 ligases, including c-Cbl and β-TrCP. Dimerized species of c-Cbl mediates β-catenin binding and its down-regulation. Wnt stimulation allows accumulation of hypophosphorylated β-catenin, which exhibits reduced binding and regulation by E3 ligases such as Jade-1 and β-TrCP. Stabilized β-catenin undergoes nuclear translocation to activate transcription of Wnt target genes (active β-catenin). In parallel, Wnt activation increases c-Cbl dimerization, binding with β-catenin, and induces c-Cbl nuclear translocation. c-Cbl destabilizes the active β-catenin in nucleus. Thus, c-Cbl is a unique E3 ligase targeting active β-catenin in nucleus.