Frizzleds and WNT/β-catenin signaling - The black box of ligand-receptor selectivity, complex stoichiometry and activation kinetics

The lipoglycoproteins of the mammalian WNT family induce β-catenin-dependent signaling through interaction with members of the Class Frizzled receptors and LDL receptor-related protein 5/6 (LRP5/6) albeit with unknown selectivity. The 10 mammalian Frizzleds (FZDs) are seven transmembrane (7TM) spanning receptors and have recently been classified as G protein-coupled receptors (GPCRs). This review summarizes the current knowledge about WNT/FZD selectivity and functional selectivity, the role of co-receptors for signal specification, the formation of receptor complexes as well as the kinetics and mechanisms of signal initiation with focus on WNT/β-catenin signaling. In order to exploit the true therapeutic potential of WNT/FZD signaling to treat human disease, it is clear that substantial progress in the understanding of receptor complex formation and signal specification has to precede a mechanism-based drug design targeting WNT receptors.