Convergent mechanisms in Wnt and Hedgehog signaling

The Wnt and Hedgehog (Hh) pathways are cornerstones of tissue and organ biology and are implicated in numerous diseases. Wnt and Hh signaling share multiple mechanistic features, including lipidated ligands, specialized ligand delivery systems, atypical G protein–coupled receptors, and transcriptional effectors controlled by phosphorylation-dependent inhibition. Here, we highlight work showing that tethered pseudosubstrate inhibition of kinases is a core mechanism governing intracellular signal transmission in both pathways. These parallels suggest that Wnt and Hh have converged on a shared regulatory logic, enabling them to encode specific functional outputs while using molecules shared with numerous other cascades. This mode of signaling may extend to other pathways where cell-surface receptors directly regulate kinase activity.