Wingless-related integration site signaling pathway (Wnt signaling pathway) (Wnt signaling)

The Wingless-related integration site (Wnt) signaling pathway is a highly conserved evolutionarily group of signal transduction pathways that regulate fundamental cellular processes including cell fate determination, proliferation, and survival [1, 3]. It is broadly classified into the canonical Wnt/beta-catenin pathway, which controls gene expression through the stabilization of beta-catenin, and non-canonical pathways that regulate cell polarity and calcium signaling [1, 2]. In the canonical cascade, Wnt ligands bind to Frizzled receptors and LRP5/6 co-receptors, inhibiting the destruction complex and allowing beta-catenin to translocate to the nucleus to activate TCF/LEF transcription factors [3, 4]. Dysregulation of this pathway is a primary driver in various malignancies, most notably colorectal cancer where APC mutations lead to constitutive activation, as well as in bone diseases and fibrosis [2, 3]. Therapeutic interventions target various nodes of the pathway, such as Porcupine inhibitors (e.g., LGK974) that block Wnt secretion and monoclonal antibodies (e.g., Vantictumab) that target Frizzled receptors [3]. However, the pathway's essential role in maintaining adult stem cell niches, particularly in the gastrointestinal tract and bone, presents significant safety challenges, including risks of bone loss and intestinal toxicity [1, 3].

Other names

Wnt/beta-catenin signalingCanonical Wnt pathwayNon-canonical Wnt pathwayWingless signalingWnt/PCP pathwayWnt/Ca2+ pathway

Drugs targeting the Wnt signaling pathway utilize several distinct mechanisms: 1) Inhibition of the O-acyltransferase Porcupine (PORCN), which is required for the palmitoylation and secretion of all Wnt ligands; 2) Monoclonal antibodies or decoy receptors that block the interaction between Wnt ligands and Frizzled receptors or LRP5/6 co-receptors; 3) Small molecule inhibitors that disrupt the interaction between beta-catenin and transcriptional co-activators like CBP; and 4) Inhibition of endogenous Wnt antagonists such as Sclerostin or DKK1 to enhance pathway activity in conditions like osteoporosis [1, 3].