Ribosomes synthesizing proteins bearing an ER signal sequence become bound to the rough ER. As translation is completed on the ER, the polypeptide chains are inserted into the ER membrane or cross it into the lumen. Some proteins (e.g., rough ER enzymes or structural proteins) remain resident in the ER. The remainder move into transport vesicles that fuse together to form new cis-Golgi vesicles. Each cis-Golgi cisterna, with its protein content, physically moves from the cis to the trans face of the Golgi stack (red arrows). As this cisternal progression occurs, many luminal and membrane proteins undergo modifications, primarily to attached oligosaccharide chains. Some proteins remain in the trans-Golgi cisternae, while others move via small vesicles to the cell surface or to lysosomes. In certain cell types (e.g., nerve cells and pancreatic acinar cells), some soluble proteins are stored in secretory vesicles and are released only after the cell receives an appropriate neural or hormonal signal (regulated secretion). In all cells, certain proteins move to the cell surface in transport vesicles and are secreted continuously (constitutive secretion). Like soluble proteins, integral membrane proteins move via transport vesicles from the rough ER to the cis-Golgi and then on to their final destinations. The orientation of a membrane protein, established when it is inserted into the ER membrane, is retained during all the sorting steps: Some segments always face the cytosol; others always face the exoplasmic space (i.e., the lumen of the ER, Golgi cisternae, and vesicles or the cell exterior). Retrograde movement via small transport vesicles retrieves ER proteins that migrate to the cis-Golgi and returns them to the ER. Similarly, cis- or medial-Golgi proteins that migrate to a later compartment are retrieved by small retrograde transport vesicles. [See B. Glick and V. Malhotra, 1988, Cell 95:883.]