Recombinant Human Frizzled-8 Fc Chimera Protein, CF

Frizzled-8 is one of at least ten seven-transmembrane (7TM) glycoproteins of the Frizzled family of Wnt receptors (1-2). Frizzled proteins are thought to be G-protein-coupled (1). Wnt engagement, with low density lipoprotein receptor-related proteins LRP-5 or LRP-6 acting as co-receptors, stabilizes beta-catenin and promotes gene transcription that is important in development and tissue maintenance (1). Human Frizzled-8 cDNA encodes 694 amino acids (aa) including a 27 aa signal peptide, a 247 aa extracellular domain (ECD), the 7TM region (aa 276-605), and a C-terminal cytoplasmic domain with a PDZ binding motif (aa 606-694) (2). The ECD includes a cysteine-rich region (CRD, aa 30-151) that binds Wnts and is highly conserved among Frizzleds, and a linker region. Within aa 28-172, human Frizzled-8 shares 99%, 99%, 90% and 85% aa identity with mouse, rat, Xenopus and zebrafish Frizzled-8, respectively. It also shares 82% aa identity with human Frizzled-5. Frizzleds can form homodimers or selective hetero-oligomers with other family members, which can involve the TM regions and possibly the CRD (1, 3). During mouse development, Frizzled-8 is expressed in tissues that are important for organizing the anterior-posterior axis (4). Interactions of Frizzled-8 with several non-Wnt ligands have been identified. Interaction with Frizzled-8 and LRP-6 allows R-spondins to activate beta-catenin signaling pathways, while interaction with IGFBP-4 (insulin-like growth factor binding protein (4) or CTGF (connective tissue growth factor) inhibits Wnt signaling (5-7). These ligands bind the extracellular CRD of Frizzled-8, blocking Wnt binding. The recombinant Frizzled-8 CRD has also been used to block Wnt signaling and inhibit growth of teratocarcinomas (5-10).