Figure 1
Overview of Wnt/β-catenin signaling. Production and secretion of Wnt ligands is dependent on the Porcupine-dependent lipid modification of Wnt and the presence of Wntless to facilitate the transport of lipid-modified Wnt to the plasma membrane (10). Once secreted, Wnt proteins bind to a receptor complex that includes either Lrp5 or Lrp6 and a member of the Frizzled family of seven-transmembrane receptors (3). In the absence of a Wnt ligand, a multiprotein complex, which includes GSK3, Axin, and APC, facilitates Casein kinase 1 (CKI)-primed and GSK3-dependent phosphorylation of β-catenin, targeting it for proteolytic degradation via the E3-ubiquitin ligase β-TrCP (11). Activation of the Wnt receptor complex leads to the activation of Dishevelled (Dvl) and the phosphorylation of the cytoplasmic domain of Lrp5/6 leading to the recruitment of Axin to the plasma membrane. This inhibits the processes, which induce the degradation of β-catenin, leading to increased accumulation in the cytoplasm. β-catenin can subsequently enter the nucleus where it can bind to members of the LEF/TCF family and activate target gene transcription via the recruitment of factors such as BCL9, Pygopus, and Parafibromin (a component of the PAF complex) to target gene promoters (12, 13). In the absence of β-catenin nuclear localization, TCF/LEF proteins can associate with members of the Groucho family to facilitate transcriptional repression. β-catenin also plays a key role in mediating cellular adhesion via its interactions with Cadherins. Finally, several extracellular inhibitors of this process, such as Dkks, Sost, and potentially Kremen, can negatively regulate the formation of the Wnt receptor complex.
