Complexity of the Wnt/β‑catenin pathway: Searching for an activation model

Wnt signaling refers to a conserved signaling pathway, widely studied due to its roles in cellular communication, cell fate decisions, development and cancer. However, the exact mechanism underlying inhibition of the GSK phosphorylation towards β-catenin and activation of the pathway after biding of Wnt ligand to its cognate receptors at the plasma membrane remains unclear. Wnt target genes are widely spread over several animal phyla. They participate in a plethora of functions during the development of an organism, from axial specification, gastrulation and organogenesis all the way to regeneration and repair in adults. Temporal and spatial oncogenetic re-activation of Wnt signaling almost certainly leads to cancer. Wnt signaling components have been extensively studied as possible targets in anti-cancer therapies. In this review we will discuss one of the most intriguing questions in this field, that is how β–catenin, a major component in this pathway, escapes the destruction complex, gets stabilized in the cytosol and it is translocated to the nucleus where it acts as a co-transcription factor. Four major models have evolved during the past 20years. We dissected each of them along with current views and future perspectives on this pathway. This review will focus on the molecular mechanisms by which Wnt proteins modulate β-catenin cytoplasmic levels and the relevance of this pathway for the development and cancer. •An overview on the extracellular regulation of Wnt ligands’ binding to their receptors and co-receptors.•Extracellular inhibitors uses different strategies to neutralize Wnts.•Most up-to-date mechanisms on how does the binding of Wnt ligands inhibit the β-catenin destruction complex.•β-catenin and the Wnt-Frizzled-LRP complex undergo endocytosis, forming a multivesicular body.•Conformational changes of Axin dictates whether it flips from an “open” conformation to a “closed” state.