Fibronectin (Fn) matrix assembly is a dynamic cellular process in which the soluble dimeric Fn molecules are assembled into insoluble, disulfide bond stabilized fibrillar polymeric matrix. Fn matrix assembly requires specific Fn binding integrins. Several Fn binding integrins that are capable of mediating Fn matrix assembly have been identified. They include α5β1, αIIbβ3 and αVβ3 integrins. Cells regulate the matrix assembly process not only by controlling cell surface expression level of the Fn binding integrins but also by modulating Fn binding and cytoskeleton binding activities of the integrins. A major challenge of the future studies is to determine the molecular mechanisms by which integrins and intracellular signalling molecules regulate extracellular Fn matrix assembly.
Vitronectin is a plasma protein which is also found in the extracellular matrix. The plasma form of vitronectin is synthesized by the liver and forms complexes with both thrombin-antithrombin and the C5b-7 complex of complement and may function as an opsonin mediating the clearance of thrombinserpin complexes from both the blood and the tissues. The functions of complexed forms of vitronectin and monomeric forms of vitronectin are distinct, in that they elicit different cellular responses perhaps by clustering unique sets of cell surface receptors. Vitronectin binds to several integrin receptors as well as to heparan sulfate proteoglycans. Under certain conditions vitronectin may be locally synthesized by tissues particularly by cells involved in migration. Vitronectin in the matrix can support cell adhesion and migration. Vitronectin expression is temporally and spatially regulated during development and is upregulated in several tumors. The αVβ3 and αVβ5 integrin receptors for vitronectin have been shown to function during angiogenesis and tumor invasion. In the extracellular matrix, vitronectin is the primary binding site for plasminogen activator inhibitor Type I and can regulate the activity and localization of urokinase-type plasminogen activator on the cell surface. The ability of vitronectin to regulate pericellular proteolysis suggests that in addition to providing a substrate for adhesion, vitronectin participates in the matrix remodeling which accompanies cell migration.
Sphingolipids are ubiquitous components of animal plasma membranes and are especially rich in nervous system. They are assumed to be present at the outer leaflet of the membrane and to be involved in a variety of biological phenomena as key molecules. Although their definitive functions remain unclear, the various aspects of their metabolism are now well defined. In mammalian cells, sphingolipids are degradated in lysosome by the sequential action of acid hydrolases. Deficiency of even one of these hydrolases causes tissue accumulation of sphingolipid and results in severe neuronal disorders, sphingolipidoses. During the past three decades, it was shown that some of the sphingolipid hydrolases require the assistance of small heat-stable nonenzymatic proteins, sphingolipid activator proteins. Four such proteins, named saposins A to D, are known. They are glycoproteins with molecular weights of 12-15kDa and show highly homologous sequence identities to each other. Importantly, all six cysteine residues in each molecule, an N-glycosylation site, and proline residues affecting turn structures are conserved at nearly identical positions. All of the cysteine residues are involved in formation of disulfide bonds. They make the structures of the saposins compact and extraordinarily stable. The resulting molecular configurations provide amphiphilic character. All four saposins are coded as separate domains in a single precursor protein, prosaposin. In this review, we describe biogenesis and function of saposins as not only the activators for sphingolipid hydrolysis but also as transporters of these lipids. In addition, we review history of the saposins, present knowledge of their functions, and prospective saposin research. We also review the recently discovered function of prosapsoin as a neurotrophic factor.
Organ regeneration (epimorphosis) differs from development in that morphogenesis occurs in a restricted region neighboring normal tissues. However, the molecular mechanisms specific to epimorphosis are unknown. Previously, we reported that regenectin, a humoral lectin from the American cockroach Periplaneta americana, appears transiently during leg regeneration and is localized around regenerating muscle cells [Kubo, T. et al. (1991) Int. J. Dev. Biol. 35, 83-90]. We recently isolated a cDNA for regenectin and examined the expression of the gene. We found that the gene was activated in the epidermis of the regenerating leg but not during the normal developmental stages. These results suggest that regenectin is specifically synthesized and secreted by the regenerating epidermis and that it plays a role in the formation of muscle in a paracrine manner. Analysis of the primary structure of regenectin revealed that regenectin belongs to the same family as LPS-binding protein, which was purified previously from Periplaneta hemolymph and which participates in the defense system. This implies that epimorphosis and the defense system share some common molecular aspects. In this minireview, we describe recent research on cockroach humoral lectins and discuss molecular mechanisms specific to epimorphosis.