Secretory sorting pathways

Many cells have an asymmetric structure because of the necessity for function (Drubin and Nelson, 1996). For example, (the outer surface of) the plasma membrane of epithelial cells is fenced by a tight junction so that the lipids are separated between the apical part and the basolateral part (Fig. 9) (Eaton and Simons, 1995). Therefore, some molecular mechanisms must exist to sort the plasma membrane proteins into these two parts. Some signals related to the secretory/endocytic pathways have been found important (Matter and Mellman, 1994). Their details are not described here because the area is too specific for predictive purposes. 

The synthesis of virtually all proteins in a cell begins on ribosomes in the cytosol (except a few mitochondrial, and in the case of plants, a few chloroplast proteins that are synthesized on ribosomes inside these organelles). The fate of a protein molecule depends on its amino acid sequence, which can contain sorting signals that direct it to its corresponding organelle. Whereas proteins of mitochondria, peroxisomes, chloroplasts and of the interior of the nucleus are delivered directly from the cytosol, all other organelles receive their set of proteins indirectly via the ER. These proteins enter the so-called secretory pathway (Fig. 1). 

Along their route through the Golgi, secretory and membrane proteins destined for the various post-Golgi pathways are intermixed. Thus, proteins of distinct routes, i.e. the endosomal and the secretory route, are sorted into individual types of transport vesicles at the TGN. Among the best characterized types of TGN-derived vesicles are clathrin-coated vesicles. In addition, several types of non-clathrin-coated vesicles have been identified but their specific functions remain to be characterized. 

In the trans Golgi compartment the peptide is sorted via secretory vesicles into a regulated pathway. In contrast to vesicles of the constitutive pathway, vesicles of the regulated pathway are stored in the cytoplasm until their stimulated release. Membrane depolarisation as well as a wide range of substances such as intracellular mediators, neuropeptides, neurotransmitters, classical hormones, cytokines, growth factors, ions and nutrients induce somatostatin secretion. General inhibitors of somatostatin release are opiates, GABA, leptin and TGF- 3. 

The biosynthetic, secretory pathway is responsible for protein sorting and delivery and allows, among other functions, for cell-cell communication through secreted products. This delivery process starts at the endoplasmic reticulum (ER), to finish in the cell plasma membrane or, in some cases, in specific intracellular organelles. To accomplish this, specific proteins must be properly directed to the correct destination, while other proteins are retained as residents within specific organelles along the way. 

All eukaryotic cells possess an unspecialized exocytic pathway known as the constitutive secretion. Vesicle membranes in this pathway fuse with the plasma membrane without any extracellular signal. As noted above, proteins destined for the secretory pathway are sorted at the level of the TGN. Proteins to be transported to the plasma membrane are directed into a constitutive secretory pathway. 

Durr G, Strayle J, Plemper R et al 1998 The medial-Golgi ion pump Pmrl supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic... 

There have been many studies designed to establish whether the endosomal pathway to lysosomes, and the recycling of receptors is the same with clathrin-dependent and clathrin-independent pinocytosis. The pathway appears to be determined in the endosome, with perhaps the lysosome being the default pathway [54]. During this sorting process, some endosomes are transported to the Golgi apparatus and become associated with secretory vesicles. 

Le Borgne, R., and Hoflack, B. (1998a). Mechanisms of protein sorting and coat assembly insights from the clathrin-coated vesicle pathway. Curr. Opin. Cell Biol. 10, 499-503. Le Borgne, R., and Hoflack, B. (1998b). Protein transport from the secretory to the endocytic pathway in mammalian cells. Biochim. Biophys. Acta 1404, 195-209. 

Recently a variety of modifiers of ubiquitin ligases have been discovered33 1 as have ubiquitin-like domains in other proteins. These findings elucidate the complexity of the sorting of proteins and removal of improperly folded and otherwise defective proteins from the secretory pathway and return to the proteasomes in the cytosol.dd ee They also suggest important roles for ubiquitination in a broad range of metabolic controls. 

Camell, L., and Moore, H.P., 1994, Transport via the regulated secretory pathway in semi-intact PC12 cells role of intra-cistemal calcium and pH in the transport and sorting of secretogranin II. J. Cell Biol. 127, 693-705... 

Durr, G., Strayle, J., Plemper, R., Elbs, S., Klee, S.K., Catty, P., Wolf, D.H., and Rudolph, H.K., 1998, The medial-Golgi ion pump Pmrl supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation. Mol. Biol. Cell 9, 1149-1162... 

Exocytosis is the secretion of proteins out of the cell across the plasma membrane into the extracellular space. Proteins destined to be secreted are synthesized on ribosomes bound to the RER membrane and are then transported in membrane-bound vesicles to the Golgi apparatus where they are sorted and packaged up into secretory vesicles. All cells continuously secrete proteins via the constitutive pathway, whereas only specialized cells (e.g. of the pancreas, nerve cells) secrete proteins via the regulated secretory pathway in response to certain stimuli. 

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