Mechanisms of Wntless trafficking and Wnt signaling

Cell to cell communication is essential during development of all animals. Several intercellular communication mechanisms have evolved, the Wnt signaling pathway is one of these communication mechanisms. Wnt signaling is required for embryonic development and adult tissue homeostasis. Misregulation of Wnt signaling can cause disease, most notably colon cancer. In my PhD studies, I have investigated the molecular mechanisms of Wnt signaling and I have investigated the mechanisms of Wnt production and secretion. Wnt is a protein that is made by specific cells in an organism. Wnt is highly hydrophobic and requires specialized machinery for export from cells. One key player is the membrane protein Wntless (Wls). Wls escorts Wnt out of the cell. Wls needs to travel between various compartments in the cell to mediate Wnt secretion; Wls travels from the Golgi apparatus to the plasma membrane. Subsequently, Wls is internalized into endosomes before Wls returns to the Golgi. I have further investigated transport step between endosomes and the Golgi. The endosomal membrane must be deformed to allow exit of Wls from endosomes. Surprisingly, we discovered that the deformation of the endosomal membranes is not mediated by proteins, but by the generation of lipid asymmetry. We have identified a protein complex that generates membrane curvature through the creation of lipid asymmetry between the two leaflets of the endosomal membrane. This protein complex is required for Wls transport from endosomes to the Golgi and for Wnt secretion.