Frizzled-4 receptor and Low-density lipoprotein receptor-related protein 5 (FZD4 and LRP5)

Frizzled-4 (FZD4) is a G protein-coupled receptor that functions as a cell-surface receptor for Wnt family ligands and the non-canonical ligand Norrin. Low-density lipoprotein receptor-related protein 5 (LRP5) is a single-pass transmembrane co-receptor that pairs with FZD4 to form a signaling complex crucial for propagating the canonical Wnt/β-catenin pathway. This receptor–co-receptor duo is essential for the development and maintenance of vasculature in the retina and inner ear, as well as for the regulation of bone mineral density in multiple tissues. Disruption of either component by mutations can result in serious inherited diseases including familial exudative vitreoretinopathy (FZD4/LRP5), osteoporosis-pseudoglioma syndrome (LRP5), and pathological angiogenesis. Due to their pivotal roles in development, homeostasis, and disease, FZD4 and LRP5 are considered validated therapeutic targets for various conditions impacting the eye, vasculature, and bone.

Other names

Frizzled class receptor 4Frizzled-4Low-density lipoprotein receptor-related protein 5LRP-5

Agonists/ligands: Norrin and Wnt proteins bind to FZD4 (and co-receptor LRP5) to activate canonical Wnt/β-catenin signaling, leading to gene transcription involved in development and tissue maintenance. Antagonists: Block reception or dimerization (e.g., anti-FZD antibodies or engineered decoy receptors) to inhibit aberrant pathway activation in cancer.