Skip to main content
. 2019 Nov 6;20(22):5525. doi: 10.3390/ijms20225525

Figure 1.

Figure 1

Wnt signal transduction. In the cytoplasm, β-catenin is phosphorylated by the complexes of GSK-3β, APC and Axin and is then rapidly degraded by the ubiquitin-proteasome system. The canonical pathway is activated by ligands, such as Wnt1 and Wnt3a, through their binding to FZD receptors and LRP5/6 complexes. Inhibition of GSK-3β induces accumulation of β-catenin in the cytoplasm. Accumulated β-catenin translocates into the nucleus and induces the expression of target genes with TCF/LEF1 and CBP. The non-canonical pathway is activated by ligands, such as Wnt5a, through their binding to FZD receptors or FZD/ Ror1/2 complexes. This binding activates the pathway without β-catenin. LRP5/6 has four BP domains (BP1 to BP4), with tertiary structures of proteins composed of β-sheets outside the cell. The BP domain is the region of Wnt ligand binding. The binding of DKK1 to the LRP5/6 receptors inhibits the canonical Wnt signaling pathway. DKK1 is known to bind to the BP1 and BP3 domains. DKK1 forms a complex with LRP5/6 and Kremen, which induces the internalization of the complex. The binding of Sclerostin to the LRP5/6 receptors also inhibits the canonical Wnt signaling pathway. Sclerostin is known to bind to the BP1 domain. The binding of Sclerostin to the LRP4 enhances its suppressive effects on the canonical Wnt signaling pathway. The sFRP family functions as a decoy receptor of Wnt, because it has the CRD that can bind Wnt ligand and inhibits both canonical and non-canonical Wnt signaling. ZNRF3 and RNF43 are target genes of the canonical Wnt signaling pathway and act as ubiquitin E3 ligases for FZD. Thus, Wnt-induced expression of ZNRF3 and RNF43 degrades FZD proteins to suppress Wnt signaling. RSPO family of secreted proteins forms a complex with the LGR, which amplifies Wnt signaling via ZNRF3/RNF43 degradation. Wnt: wingless-related MMTV integration site, GSK-3β: glycogen synthase kinase-3 β, APC: adenomatous polyposis coli, FZD: frizzled, LRP: low-density lipoprotein-related receptor, TCF; T-cell factor, LEF1: lymphocyte enhancer factor 1, CBP: CREB-binding protein, Ror1/2: receptor tyrosine kinase-like orphan receptor 1/2, BP domains: β-propeller domains, DKK: dickkopf, sFRP: secreted frizzled-related protein, CRD: cysteine-rich domain, ZNRF3: zinc and ring finger 3, RNF43: ring finger 43, RSPO: roof-plate specific spondin, LGR: leucine-rich repeat-containing G protein-coupled receptor.