FZDs

FZDs, short for Frizzled receptors, refer to a family of Wnt receptors that play central roles in regulating cell fate, proliferation, polarity, and movement. In humans, the family comprises ten genes (FZD1 through FZD10), and their protein products function as seven-pass transmembrane receptors related to G protein-coupled receptors. A key feature is an extracellular cysteine-rich domain that binds Wnt ligands, followed by the seven transmembrane segments and a cytoplasmic C-terminal tail containing a KTxxxW motif that recruits signaling partners, notably Dishevelled.

FZDs participate in two main signaling modes. The canonical Wnt/beta-catenin pathway requires binding of Wnt to FZD together with the LRP5/6 co-receptor, leading to stabilization and nuclear translocation of beta-catenin and activation of TCF/LEF target genes. Noncanonical pathways operate independently of beta-catenin and can drive planar cell polarity or Wnt/Ca2+ signaling, influencing cytoskeletal organization, cell movement, and calcium signaling. The choice of pathway depends on the specific FZD, the ligand, and cellular context, with substantial cross-talk and redundancy among family members.

Physiological roles include embryonic development, tissue homeostasis, stem cell maintenance, and regeneration. Dysregulation of FZDs or Wnt signaling is linked to diseases, most notably various cancers, developmental disorders, and neurodegenerative conditions. Because of their central role in signaling, FZDs are common targets of research aimed at understanding development and exploring therapeutic interventions for Wnt-related diseases.