An itch for things remote: The journey of Wnts

Wnts are a family of secreted, lipid-modified signaling glycoproteins that regulate a multiplicity of fundamental biological processes. Wnt signaling is essential for embryonic development, controlling body axis patterning, cell proliferation, cell migration and cell fate specification needed for proper tissue and organ formation. In adulthood, Wnt signaling controls tissue regeneration in a wide range of organs, and disturbance of this system is common in cancer and other diseases. A key feature of Wnt signaling is that it is a local process. Wnts signal via paracrine, cell-to-cell communication. Upon synthesis and transport to the plasma membrane in the "sending" cell, Wnts travel to nearby "receiving" cells. At the plasma membrane of these receiving cells, they interact with a variety of cell-surface receptors. This interaction triggers a diversity of different downstream signaling events, including the stabilization of β-catenin and tissue-specific changes in gene expression. Wnt signaling is a local event because as an indispensable step in their maturation, Wnts are palmitoleated immediately after synthesis. This lipid modification is essential for Wnts to be transported and biologically active, but it also renders them highly hydrophobic. This makes all Wnts highly dependent on carrier proteins and specialized cellular structures both for intra- and inter-cellular movement. How this complex machinery acts in concert to deliver its highly important payload from the place of synthesis to the correct site of delivery is under active investigation. Here, we review the current understanding of how lipid-modified Wnts are processed, transported, and guided to their place of action.