Fzd

FZD, or frizzled, refers to a family of Wnt receptors that play a central role in Wnt signaling across animals. In humans, there are ten FZD genes (FZD1–FZD10) encoding seven‑transmembrane receptors with a distinctive N‑terminal cysteine‑rich domain that binds Wnt ligands. The receptors are GPCR‑like in structure, with a cytoplasmic region that interacts with intracellular signaling proteins to propagate signals.

Frizzled receptors bind secreted Wnt proteins, often in conjunction with co‑receptors such as LRP5/6 for canonical signaling. Binding initiates two broad signaling programs: canonical Wnt/β‑catenin signaling, and noncanonical pathways that regulate cell polarity, migration, and calcium signaling. In canonical signaling, Wnt binding to FZD‑LRP complexes inhibits the β‑catenin destruction complex, allowing β‑catenin to accumulate and enter the nucleus to regulate target gene transcription via TCF/LEF transcription factors. Noncanonical signaling pathways operate largely independently of β‑catenin and involve distinct downstream effectors, including JNK and calcium‑mediated processes.

Functional roles of FZD receptors are diverse and essential for embryonic development, tissue homeostasis, and stem cell maintenance. They influence cell fate decisions, processes such as cell migration and polarity, and organogenesis. Disruption or misregulation of FZD signaling has been implicated in various diseases, including cancers, fibrotic disorders, and neurodevelopmental conditions.

Because of their central position in Wnt signaling, FZD receptors are a focus of therapeutic research. Strategies under investigation include decoy receptors and monoclonal antibodies that block Wnt–FZD interactions, as well as approaches aiming to modulate specific FZD subtypes to achieve targeted clinical effects. Research continues to refine understanding of subtype-specific roles and therapeutic potential.