Figure 3

Simplified overview of the canonical Wnt signaling pathway. The typical mammalian genome harbors 19 genes encoding Wnt secretory factors and 10 Frizzled (Fzd) genes encoding their receptors. Two low-density lipoprotein receptor-related proteins (Lrp) 5 or 6 act as Fzd co-receptors. Activating combinations of Fzd/Lrp/Wnt initiate signaling activity by silencing the activity of a dedicated β-catenin (βcat) destruction complex. Dvl gene products are instrumental in achieving this. (a) In the absence of Wnt signals, constitutively synthesized cytoplasmic βcat is the immediate target of this complex. Essential components of this complex are two tumor suppressor proteins: Apc (adenomatous polyposis coli) and axin, which act as scaffolds to capture newly synthesized βcat and allow its phosphorylation by the constitutively active kinases casein kinase-1 (Ck1) and glycogen synthase kinase 3 (GSK3), also residing in this complex. (b) The Wnt-binding-induced cytoplasmic accumulation of βcat leads to import into the nucleus and binding to T-cell transcription factor (Tcf)/Lef transcription factors, upon replacement of the transcriptional Groucho repressors. Bipartite Tcf/Lef-βcat complexes are the ultimate effectors of this signaling cascade. A series of secreted antagonists control signaling activity at the level of ligand perception. Secreted Frizzled-related proteins (Sfrp1, 2, 4 and 5), Frzb and Wnt inhibitory factor (Wif) can bind Wnt directly and prevent it from activating their receptors [83–86]. The other Wnt antagonists, Dickkopf 1 (Dkk1) [87] and Wise [88], inhibit by binding to the Lrp co-receptor. R-spondins, also operating at this level, are unique in enhancing Wnt activity. The seven transmembrane Lgr (4, 5 and 6) receptors mediating their action were recently uncovered [48, 89, 90].