Figure 7

Model of Rad6B/β-catenin regulation in breast cancer cells with autocrine Wnt activity. Activation of the canonical Wnt pathway is regulated by Wnt ligand interactions with Wnt receptors Frizzled (FZD) and coreceptors LRP5/6 at the cell surface, and culminates in β-catenin stabilization by preventing its recruitment into the APC/Axin/GSK3 destruction complex. Rad6B transcription is induced by β-catenin, and Rad6B in turn stabilizes β-catenin by mediating K63 linked polyubiqitin modifications that render β-catenin insensitive to proteasomal degradation. Rad6B silencing disrupts the positive feedback loop between Rad6B expression and β-catenin stabilization with resultant decrease in ubiquitinated β-catenin and β-catenin transcriptional activity. The Rad6B induced β-catenin stabilization occurs downstream of Wnt activation and requires LRP6 mediated protection of β-catenin from incorporation into the destruction complex, as inhibition of LRP6 function in Rad6B overexpressors prevents β-catenin stabilization with resultant decreases in Rad6B expression.