Members of the selectin family of adhesion molecules are predominantly responsible for mediating the binding of leukocytes to activated endothelium. This family of structurally related proteins contains three members: E-selectin, which is expressed by activated vascular endothelium; L-selectin, which is expressed by leukocytes, and P-selectin, which is expressed by activated endothelium and activated platelets. These adhesion molecules bind to multiple carbohydrate ligands which are presented to them by glycoproteins and/or glycolipids. Here, the currently proposed ligands of the selectins are reviewed.

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The thrombospondins(TS) are a family of proteins which appear to be involved in the acute regulation of the migration, adhesion and proliferation of a number of cell types. The proteins consist of modular domains, at least four of which contain cellular binding sites. One of these sites in the amino terminal heparin binding domain binds heparin and similar sulfated glycans. The three other sites reside in linear peptide sequences. One of these is the RGDA sequence within the calcium binding domain. A second site was recently identified in the properdin-like repeats of TS and contains the sequnce CSVTCG. This appears to be a “compound” adhesive site in that it is immediately followed by a cluster of positively charged amino acids that may bind sulfated glycans, and is preceded by a WXXWXXW motif conserved in several homologues of TS. The C terminal domain of TS appears to contain another cell adhesive site that is independent of the nearby RGD sequence. The binding of cells to this C terminal peptide site may be augmented by a nearby heparin binding site as well. Receptors have been tentatively identified for all of these sites.

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The growth control of non-transformed mammalian cells is under the stringent control of the actual cell density. With increasing cell densities, proliferation progressively decreases and eventually ceases at confluency. We have isolated a plasma membrane glycoprotein, referred to as contactinhibin, which is responsible for the contact-dependent inhibition of growth of human diploid fibroblast. It inhbits the proliferation of sparsely seeded cells in a reversible, non-toxic manner in immobilised form at pmolar concentrations, while in soluble form it is inactive. The biologically active moiety resides exclusively within the N-glycosidically linked glycans. In addition, for an efficient inhibition of growth, terminal β-glycosidically linked galactose residues have to be present on the N-glycans. By culturing human fibroblasts in the presence of anti-contactinhibin-antibodies the cells grow to 2 fold higher saturation density, together with an extentive criss-cross and focal growth pattern. Contactinhibin, interacts specifically with a plasma membrane receptor, whose binding activity is inversely regulated by the extent of phosphorylation. Cancer growth is suggested to arise from an overphosphorylation of the contactinhibin-receptor.

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Lectins are widely distributed in extracts of stems from woody plants. They are localized in the vacuole or protein bodies of phloem parenchyma existing in the inner bark. Lectins in the bark show an annual rhythm in that they decrease in spring and increase in the autumn. Therefore, it is suggested that lectins in bark have a function for the storage of nutrients. During the active period of secondary growth, from May to August, lectin decreased mainly in the outermost region of inner bark where the cork tissue differentiates and dilatation (see middle of the second paragraph in Chapter C) occurs. This result suggests that lectin is consumed in the process of cork tissue differantiation and/or dilatation. Recently, unique lectins in their binding specificities were found in barks. One binds to N-acetylneuraminic acid-containing oligosaccharides and the other binds to mannose, although most of the bark lectins bind to either N-acetylglucosamine or N-acetylgalactosamine. It has been hypothesized that lectins specific for N-acetylglucosamine and N-acetylneuraminic acid function as a defense system. However, the exact function of lectin in tree stems has not yet been established.

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Gangliosides occur most prominently in the neuron where they comprise the major type of sialoglyconjugate in the plasma membrane. They contain one to several sialic acids and consist of a large group of molecular species divided into several families. The gangliotetraose family predominates in mature neurons. This series makes its appearance during neurite outgrowth and synaptogenesis, replacing the simpler structures that occur prior to differentiation. Current research suggests that gangliosides function primarily as modulators of membrane proteins, including certain enzymes, receptors, ion channels, and cell adhesion molecules. A recent example is the excitatory opioid receptor, whose activity is potentiated specifically by GM₁. A number of other receptors have been shown to be associated with and modulated, either positively or negatively, by various other gangliosides. Calcium transport is affected in a bidirectional manner by GM₁, and some of the trophic effects of the latter can be explained by such activity. Pronounced morphological changes--e.g., neuritogenesis, fasciculation, blockade of neurite outgrowth-- are observed in vitro on addition of gangliosides, or interventive agents which affect endogenous gangliosides. Trophic effects due to administered gangliosides are also seen in vivo but apparently via different mechanisms.

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Type VIII collagen was initially characterized as a biosynthetic product of bovine aortic endothelial cells in vitro and thus named Endothelial Collagen(EC). The protein has now been identified in avian and mammalian species as a product secreted by cultured corneal endothelial cells, keratinocytes, fibroblasts, astrocytoma and other tumor cells, and endothelial cells derived from several classes of blood vessels. In vivo, the distribution of type VIII collagen is restricted to specialized extracellular matrices such as meninges, periosteum, perichondrium, and Descemet's membrane of the cornea. It is also present in the subendothelium of large and small blood vessels and has been localized in capillary-like structures formed by sprouting cultures of endothelial cells. Data from protein and nucleotide sequencing have identified two distinct chains, termed α1 (VIII) and α2 (VIII); however, the assembly of these chains in the extracellular space is still poorly understood. Protein extracts from Descemet's membrane indicate that, in this tissue, type VIII collagen is a heterotrimer. Our understanding of the biological role of type VIII collagen is rather limited. Although type VIII collagen seems to perform a structural role in the Descemet's membrane, its temporally and spatially restricted expression during development suggests an involvement in tissue remodeling and differentiation.

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Lysosomal proteins are synthesized at the rough ER and initially follow the secretory pathway. En route to the Golgi, mannose 6-phosphate residues (M6P) are attached to N-linked oligosaccharides of soluble lysosomal proteins and serve as a sorting signal. In the Golgi, lysosomal proteins are separated from the secretory pathway by binding to mannose 6-phosphate receptors (MPR). The receptor-ligand complexes are delivered via clathrin-coated vesicles to an acidified prelysosomal compartment, where due to a low pH the MPR-ligand complexes dissociate. Lysosomal proteins are subsequently sorted into dense lysosomes, while the receptors return to the Golgi or the plasma membrane and are available for further rounds of transport. Extracellular ligands can be internalized by MPR located at the plasma membrane. Two types of MPR of molecular sizes of 300 and 46kDa are known. While the two receptors show similar binding properties for M6P-ligands, most of the intracellular sorting is accomplished by the MPR 300. Furthermore, only the MPR 300 endocytoses extracellular ligands from the cell surface and this type of receptor contains, in many species, an additional binding site for the insulin-like growth factor II (IGF II)

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