Figure 7.

Wnt signaling pathways. Wnt ligands can transduce their signal through at least three Frizzled-dependent (Fz) pathways: the canonical, the calcium, and the PCP pathways, all of which involve the activation of Dishevelled (Dvl). The canonical pathway requires the co-receptors Lrp5/6 to recruit Dvl and inhibit the “destruction complex” composed of Adenomatous polyposis coli (APC), Axin, and Glycogen synthase 3β (GSK3β). Wnt binding leads to the phosphorylation of GSK3β in this complex and, as a consequence, to the accumulation of unphosphorylated β-catenin, which can enter the nucleus and together with the transcription factors Tcf/Lef induce the expression of target genes. Activation of the calcium pathway results in an increase of cytosolic calcium (Ca²⁺) and the subsequent activation of calcium-dependent kinases (CaMKII). In the PCP pathway, activation of the transmembrane proteins Vangl, Celsr, and PTK7 and the recruitment of the intracellular proteins Prickle and Daam lead to activation of Rho GTPases and JNK, promoting cytoskeleton remodeling. More recently, Fz-independent Wnt signaling has been described. Wnt ligands can bind directly to receptors such as Ryk or Ror. The intracellular signaling cascades activated in these cases are poorly understood.