Wnt signaling signaling at and above the receptor level

Wnt signaling is one of the most important developmental signaling pathways that controls cell fate decisions and tissue patterning during early embryonic and later development. It is activated by highly conserved Wnt proteins that are secreted as palmitoylated glycoproteins and act as morphogens to form a concentration gradient across a developing tissue. Wnt proteins regulate transcriptional and posttranscriptional processes depending on the distance of their origin and activate distinct intracellular cascades, commonly referred to as canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) pathways. Therefore, the secretion and the diffusion of Wnt proteins needs to be tightly regulated to induce short- and long-range downstream signaling. Even though the Wnt signaling cascade has been studied intensively, key aspects and principle mechanisms, such as transport of Wnt growth factors or regulation of signaling specificity between different Wnt pathways, remain unresolved. Here, we introduce basic principles of Wnt/Wg signal transduction and highlight recent discoveries, such as the involvement of vacuolar ATPases and vesicular acidification in Wnt signaling. We also discuss recent findings regarding posttranslational modifications of Wnts, trafficking through the secretory pathway and developmental consequences of impaired Wnt secretion. Understanding the detailed mechanism and regulation of Wnt protein secretion will provide valuable insights into many human diseases based on overactivated Wnt signaling.