Choosing the right input in cell signaling

Over the evolutionary history of multicellular animals, several ancient signaling pathways have been conserved and reused for a myriad of functions. One such pathway is the Wnt signaling pathway, the almost ubiquitous roles of which include vital processes such as organogenesis, stem cell maintenance, and regeneration (1). This diversity of functions of the Wnt pathway may explain the diversity of ligands and receptors that activate these processes. In humans, there are 19 Wnt ligands, 10 Frizzled (FZD) receptors, and two lipoprotein receptor–related protein (LRP) co-receptors, as well as other receptors, such as RAR-related orphan receptor and receptor-like tyrosine kinase (2). Despite this diversity, binding interactions between Wnt ligands and FZD receptors are highly conserved (1), so that multiple Wnt ligands can bind to a FZD, and each Wnt ligand can bind to multiple FZDs to elicit cellular responses (3). Given this promiscuity, it is an ongoing pursuit to understand how cells can selectively respond to a specific Wnt ligand. On page 663 of this issue, Eubelen et al. (4) pursue this question and resolve the mechanism of how WNT7 selectivity is achieved. Resolving the mechanism for ligand discrimination has implications for understanding information flow in cell signaling and reveals new therapeutic opportunities