The complex web of canonical and non‐canonical Hedgehog signaling

Abstract Hedgehog (Hh) signaling is a widely studied signaling pathway because of its critical roles during development and in cell homeostasis. Vertebrate canonical and non‐canonical Hh signaling are typically assumed to be distinct and occur in different cellular compartments. While research has primarily focused on the canonical form of Hh signaling and its dependency on primary cilia – microtubule‐based signaling hubs – an extensive list of crucial functions mediated by non‐canonical Hh signaling has emerged. Moreover, amounting evidence indicates that canonical and non‐canonical modes of Hh signaling are interlinked, and that they can overlap spatially, and in many cases interact functionally. Here, we discuss some of the many cellular effects of non‐canonical signaling and discuss new evidence indicating inter‐relationships with canonical signaling. We discuss how Smoothened (Smo), a key component of the Hh pathway, might coordinate such diverse downstream effects. Collectively, pursuit of questions such as those proposed here will aid in elucidating the full extent of Smo function in development and advance its use as a target for cancer therapeutics.