A cell capable of regulated secretion must separate at least three classes of proteins before they leave the TGN—those destined for lysosomes (via endosomes), those destined for secretory vesicles, and those destined for immediate delivery to the cell surface (Figure 13–63). We have already discussed how proteins destined for lysosomes are tagged with M6P for packaging into specific departing vesicles, and analogous signals are thought to direct secretory proteins into secretory vesicles. The nonselective constitutive secretory pathway transports most other proteins directly to the cell surface. Because entry into this pathway does not require a particular signal, it is also called the default pathway. Thus, in an unpolarized cell such as a white blood cell or a fibroblast, it seems that any protein in the lumen of the Golgi apparatus is automatically carried by the constitutive pathway to the cell surface unless it is specifically returned to the ER, retained as a resident protein in the Golgi apparatus itself, or selected for the pathways that lead to regulated secretion or to lysosomes. In polarized cells, where different products have to be delivered to different domains of the cell surface, we shall see that the options are more complex.
secretory vesicles bud from the Trans golgi network
Cells that are specialized for secreting some of their products rapidly on demand concentrate and store these products in secretory vesicles (often called dense-core secretory granules because they have dense cores when viewed in the electron microscope). Secretory vesicles form from the TGN, and they release their contents to the cell exterior by exocytosis in response to specific signals. The secreted product can be either a small molecule (such as histamine or a neuropeptide) or a protein (such as a hormone or digestive enzyme).
Proteins destined for secretory vesicles (called secretory proteins) are packaged into appropriate vesicles in the TGN by a mechanism that involves the selective aggregation of the secretory proteins. Clumps of aggregated, electron-dense material can be detected by electron microscopy in the lumen of the TGN. The signals that direct secretory proteins into such aggregates are not well defined and may be quite diverse. When a gene encoding a secretory protein is artificially expressed in a secretory cell that normally does not make the protein, the foreign protein is appropriately packaged into secretory vesicles. This observation
Figure 13–62 The constitutive and regulated secretory pathways. The two pathways diverge in the Tgn. The constitutive secretory pathway operates in all cells. Many soluble proteins are continually secreted from the cell by this pathway, which also supplies the plasma membrane with newly synthesized membrane lipids and proteins. specialized secretory cells also have a regulated secretory pathway, by which selected proteins in the Tgn are diverted into secretory vesicles, where the proteins are concentrated and stored until an extracellular signal stimulates their secretion. The regulated secretion of small molecules, such as histamine and neurotransmitters, occurs by a similar pathway; these molecules are actively transported from the cytosol into preformed secretory vesicles. There they are often bound to specific macromolecules (proteoglycans, for histamine) so that they can be stored at high concentration without generating an excessively high osmotic pressure.
Figure 13–63 The three best-understood pathways of protein sorting in the trans Golgi network. (1) proteins with the mannose 6-phosphate (M6p) marker (see figure 13–45) are diverted to lysosomes (via endosomes) in clathrin-coated transport vesicles. (2) proteins with signals directing them to secretory vesicles are concentrated in such vesicles as part of a regulated secretory pathway that is present only in specialized secretory cells. (3) In unpolarized cells, a constitutive secretory pathway delivers proteins with no special features to the cell surface. In polarized cells, such as epithelial cells, however, secreted and plasma membrane proteins are selectively directed to either the apical or the basolateral plasma membrane domain, so a specific signal must mediate at least one of these two pathways, as we discuss later.