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

Eur J Pharmacol. 2015 Sep 15;763(Pt B):191-5. doi: 10.1016/j.ejphar.2015.05.031. Epub 2015 May 21.


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.

Keywords: Canonical signaling; Class Frizzled; GPCR; LRP5/6; Receptor complex.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Frizzled Receptors / chemistry
  • Frizzled Receptors / metabolism*
  • Humans
  • Kinetics
  • Ligands
  • Protein Multimerization
  • Substrate Specificity
  • Wnt Signaling Pathway*


  • Frizzled Receptors
  • Ligands