Retromer and sorting nexins in development

Trafficking and signaling processes involve common molecular components. The machinery that controls intracellular trafficking is vital in ensuring that signaling mechanisms take place correctly. An illustrative example of this relationship is the sustained signaling of endocytosed membrane receptors, such as receptor Tyr kinases and G-protein coupled receptors, after ligand-induced activation. An intriguing role in controlling the fate of these and other receptors at the endosome has been attributed to members of the sorting nexin protein family. The best characterized sorting nexins are subunits of a multimeric complex, termed retromer. It was first found in yeast that retromer mediates endosome-to-Golgi retrieval of receptors after they have delivered soluble hydrolase precursors into the vacuole, the organelle equivalent to the mammalian lysosome. Work in cultured mammalian cells later demonstrated that retromer performs an analogous function in higher eukaryotes. Data from genetically modified mice, and from a simpler organism such as the nematode Caenorhabtidis elegans, has revealed that retromer performs an essential role during embryogenesis. This review will discuss implications of recent work on this subject.