Frizzleds as GPCRs - More Conventional Than We Thought!

For more than 30 years, WNT/β-catenin and planar cell polarity signaling has formed the basis for what we understand to be the primary output of the interaction between WNTs and their cognate receptors known as Frizzleds (FZDs). In the shadow of these pathways, evidence for the involvement of heterotrimeric G proteins in WNT signaling has grown substantially over the years - redefining the complexity of the WNT signaling network. Moreover, the distinct characteristics of FZD paralogs are becoming better understood, and we can now apply concepts valid for classical GPCRs to grasp FZDs as molecular machines at the interface of ligand binding and intracellular effects. This review discusses recent developments in the field of WNT/FZD signaling in the context of GPCR pharmacology, and identifies remaining mysteries with an emphasis on structural and kinetic components that support this dogma shift.