Figure 1. Crosstalk between Wnt signaling and the Androgen Receptor.

A simplified view of canonical Wnt signaling: Cytoplasmic β-catenin (βcat), when not bound to E-cadherin at the cell membrane, is phosphorylated by GSK-3 in complex with the proteins adenomatous polyposis coli (APC) and Axin. Phosphorylated β-catenin is then ubiquitinated and degraded by the proteasome. In the presence of a Wnt extracellular signal, through Frizzled receptors in complex with LRP, disheveled (DVL) inhibits the β-catenin phosphorylation complex. This stabilizes β-catenin which translocates to the nucleus activating transcription factors of the TCF/LEF family. Multiple intersections of the Wnt pathway have been shown in PCa: 1- β-catenin binds AR directly and can enhance its transcriptional activity; 2- the AR can be recruited to the promoter of TCF/LEF target genes like CycD1 and Myc; 3- β-catenin/TCF bind to the promoter of AR itself, activating AR mRNA transcription; 4- β-catenin/TCF target gene CycD1 can inhibit AR mediated transcription; and 5- GSK-3 can phosphorylate AR leading to a decrease in AR mediated transcription (Amir et al., 2003; Kypta and Waxman, 2012; Mazor et al., 2004; Pawlowski et al., 2002; Petre et al., 2002; Salas et al., 2004; Song et al., 2003; Wang et al., 2004; Yang et al., 2002; Yang et al., 2006).