Wnts

Wnts are a family of secreted signaling proteins that regulate cell fate, proliferation, migration, and polarity during embryonic development and in adult tissues. The name Wnt comes from a combining of the Drosophila gene wingless and the mammalian int-1. Wnts are cysteine-rich, lipid-modified glycoproteins that undergo post-translational modification by the enzyme porcupine, which enables their secretion and range of signaling activity.

Wnt signaling operates through multiple pathways, the best known being the canonical Wnt/β-catenin pathway and several noncanonical routes. In the canonical pathway, Wnt binds to a receptor complex consisting of Frizzled receptors and LRP5/6 co-receptors. This interaction inhibits the β-catenin destruction complex, leading to stabilization and accumulation of β-catenin in the cytoplasm, its translocation to the nucleus, and activation of Wnt target genes with TCF/LEF transcription factors. Noncanonical Wnt signaling can proceed independently of β-catenin and includes the planar cell polarity pathway and the Wnt/Ca2+ pathway, which influence cytoskeletal dynamics, cell movement, and intracellular calcium signaling.

Receptors and modulators shape the response. Frizzled family receptors (FZD1-10) cooperate with co-receptors such as LRP5/6, and sometimes ROR1/2 or Ryk in noncanonical signaling. Secreted antagonists such as DKK proteins, sFRPs, and WIF1 can dampen signaling, while RSPO proteins can amplify it by enhancing receptor availability. The Wnt system is tightly regulated and highly conserved across species.

Physiological roles are broad, including embryogenesis, stem cell maintenance, tissue regeneration, bone formation, and neural development. Dysregulation is associated with developmental disorders and cancers, making Wnt signaling a major focus of biomedical research.