At the TIPS journal club meeting held on December 31, 2018, the topic of “Wnt signaling pathways” was presented by Madiha Khalid. A summary of this presentation is in below.
Wnt signaling pathways characterized into canonical (β-catenin dependent) and noncanonical (β-catenin independent). Canonical Wnt signaling or Wnt/β-catenin signaling regulates cell fate determination during development. An absence of Wnt protein extracellularly results into activation of β-catenin destruction complex which consists of two scaffold proteins i.e. Axin and APC and two kinases enzymes i.e. CK1 and GSK3 responsible for β-catenin phosphorylation at its amino terminus. Phosphorylated β-catenin recognized by F-box protein β-TrCP which along SCF ubiquitin ligase ubiquitinates β-catenin leading to its proteolysis by the proteasome. This results into the low β-catenin level and preventing its translocation to the nucleus thereby repressing Wnt target genes by the DNA-bound TCF/LEF. In the presence of Wnt protein extracellularly, it forms a Wnt-Fz-LRP6/5 complex upon binding to Fz receptor and its co-receptors LRP6/5. Wnt-Fz-LRP6/5 complex recruit cytosolic protein Dv1 engaging Axin along kinases enzymes CK1 and GSK3 which in turn phosphorylate cytosolic tail of LRP6/5. The phosphorylation of cytosolic tail act as positive feedback causing sequestration of β-catenin destruction complex consequently stabilizing and accumulating cytoplasmic β-catenin to enter into the nucleus to form complexes with TCF/LEF and finally activating Wnt target gene expression.