Frizzled receptor family (FZD)

The Frizzled receptor family (FZD1–10) consists of ten seven-pass transmembrane proteins that serve as the primary receptors for secreted Wnt signaling ligands [1, 10]. Classified as Class F G protein-coupled receptors (GPCRs), these receptors feature a conserved extracellular N-terminal cysteine-rich domain (CRD) that is essential for high-affinity binding to Wnt proteins [5, 13]. Frizzled receptors mediate critical cellular processes, including the canonical Wnt/beta-catenin pathway, which regulates cell fate and proliferation, and non-canonical pathways like planar cell polarity (PCP), which governs tissue architecture [3, 12]. In clinical contexts, dysregulated Frizzled signaling is strongly associated with the progression of various malignancies, including breast, colorectal, and pancreatic cancers, where it promotes cancer stem cell maintenance and metastasis [1, 13]. Consequently, Frizzled receptors have become significant therapeutic targets, leading to the development of monoclonal antibodies like vantictumab and decoy receptors like ipafricept [6, 11]. However, a major challenge in targeting this family is the occurrence of target-mediated toxicities, particularly bone fractures, due to the fundamental role of Wnt signaling in maintaining bone density and adult tissue homeostasis [6, 14].

Other names

Frizzled-class G protein-coupled receptorsFZD receptorsWnt receptorsFrizzled family

Antagonism of Wnt ligand binding to the extracellular cysteine-rich domain (CRD), thereby inhibiting downstream canonical Wnt/beta-catenin signaling and non-canonical pathways such as planar cell polarity (PCP) and Wnt/calcium signaling [1, 10, 13].