Fig. 1

Wnts signal through a “canonical” pathway involving β-catenin mediated transcriptional regulation (at left) and through “non-canonical” pathways involving calcium and Rac/JNK-mediated signaling (at right). In the absence of Wnt, the β-catenin destruction complex, whose core members are the scaffold proteins axin and adenomatous polyposis coli (APC) and the protein kinase glycogen synthase kinase 3β (GSK3β), binds and phosphorylates β-catenin. Phospho-β-catenin is then ubiquitinated and destroyed in the proteosome. Wnt binding to Fzd and LRP5/6 activates Disheveled, which breaks up the β-catenin destruction complex. This leads to accumulation of β-catenin in the cytosol and translocation of β-catenin into the nucleus, where it forms complexes with LEF/TCF transcription factors to promote transcription of selected gene targets. Wnt binding to Fzd can also trigger the Wnt/calcium signaling pathway involving calcium-dependent activation of CamK and PKC, or to the Wnt/PCP signaling pathway which leads to regulation of small GTPases and JNK. Wnt signaling is inhibited extracellularly by Dkk proteins, which specifically bind to LRP5/6 and thereby antagonize only Wnt/β-catenin signaling, or by secreted Frizzled-related proteins (SFRPs) and Wnt inhibitory factor (WIF), which bind Wnts extracellularly to antagonize all Wnt-activated signaling pathways