Bi-directional trafficking

The trans-Golgi network (TGN) is the major sorting station of the biosynthetic pathway, in which newly synthesized soluble and transmembrane proteins, as well as lipids, are sorted for subsequent transport to different destinations: the cell surface (apical and basolateral in polarized cells), secretory granules in endocrine cells, or the endosomal system. Several transmembrane proteins have been used as markers in studies of protein sorting at the TGN in mammalian cells. One can distinguish two classes of transmembrane protein. The first comprises proteins that are in dynamic equilibrium between the TGN, endosomes and the plasma membrane, and therefore undergo multiple rounds of protein sorting. The mannose 6phosphate receptors (MPRs) are one example of this type of protein. At the TGN, MPRs sort newly synthesized, soluble lysosomal hydrolases, which are then routed to endosomes. Here, the hydrolases dissociate from their receptors and subsequently reach lysosomes. The MPRs are retrieved from endosomes and recycle back to the TGN, where they enter a new round of transport (Mellman, 1996). The endoprotease furin and the transmembrane protein TGN38 follow a similar complex transport pattern. In contrast, the second class of transmembrane protein is sorted in the TGN but does not recycle to this compartment. Examples of this class of protein are the lysosomal membrane glycoproteins Lamp and Limp. The study of the trafficking of these proteins has provided strong evidence for the existence of multiple, parallel transport pathways between the TGN and endosomes in both anterograde and retrograde directions (Fig. 1). The existence of multiple vesicular transport steps raises the question of how proteins are sorted into distinct transport intermediates. The cytoplasmic domains of transmembrane proteins contain tyrosine and dileucine-based sorting signals that drive the segregation of proteins into transport intermediates (Bonifacino and Dell’Angelica, 1999; Kirchhausen, 1999; Schmid, 1997). These sorting signals interact with multimeric assembly or adaptor protein complexes (APs) that form part of the coat of transport vesicles. At least four distinct APs exist and bind to membranes in a compartment-specific manner. Adaptor proteins not only serve as structural components of vesicle coats but also 2093 Journal of Cell Science 113, 2093-2101 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 JCS0740