No abstract

Proteoglycans that modulate the activities of growth factors, chemokines, and coagulation factors regulate in turn the vascular endothelium with respect to processes such as inflammation, hemostasis, and angiogenesis. Endothelial cell-specific molecule-1 is mainly expressed by endothelial cells and regulated by pro-inflammatory cytokines (Lassalle, P., Molet, S., Janin, A., Heyden, J. V., Tavernier, J., Fiers, W., Devos, R., and Tonnel, A. B. (1996) J. Biol. Chem. 271, 20458 -20464). We demonstrate that this molecule is secreted as a soluble dermatan sulfate (DS) proteoglycan. This proteoglycan represents the major form either secreted by cell lines or circulating in the human bloodstream. Because this proteoglycan is specifically secreted by endothelial cells, we propose to name it endocan. The glycosaminoglycan component of endocan consists of a single DS chain covalently attached to serine 137. Endocan dose-dependently increased the hepatocyte growth factor/scatter factor (HGF/SF)-mediated proliferation of human embryonic kidney cells, whereas the nonglycanated form of endocan did not. Moreover, DS chains purified from endocan mimicked the endocan-mediated increase of cell proliferation in the presence of HGF/SF. Overall, our results demonstrate that endocan is a novel soluble dermatan sulfate proteoglycan produced by endothelial cells. Endocan regulates HGF/SF-mediated mitogenic activity and may support the function of HGF/SF not only in embryogenesis and tissue repair after injury but also in tumor progression.In the last few years, the vascular endothelium has been shown to play a crucial role in inflammation, coagulation, angiogenesis, and tumor invasion, primarily through the fine regulation of receptor-ligand interactions and secretion of different mediators. Endothelial cells also express several proteoglycans such as decorin, biglycan, PG-100, glypican, and members of the syndecan family that regulate intercellular interactions and activation processes.Proteoglycans are complex macromolecules that consist of a polypeptide with one or more glycosaminoglycan chains covalently bound to a serine (or rarely a threonine) residue. Different families of proteoglycans have been described (1-3) as follows: heparan sulfate, chondroitin sulfate, dermatan sulfate, and keratan sulfate proteoglycans. Heparan sulfate proteoglycans have come to particular prominence recently because of their multiple regulatory interactions with growth factors, enzymes, enzyme inhibitors, and components of the extracellular matrix (4, 5). Dermatan sulfate proteoglycans (DSPGs) 1 from human fluids become of particular importance during inflammation and response to injury (6 -11), contributing, for example, to the majority of the FGF-2-dependent cell proliferation involved in the regulation of wound repair (6). DSPGs are also known to bind to many HS-binding proteins, including FGF-2, interleukin-7 (12), platelet factor 4 (13), fibronectin (14), and heparin cofactor II (15). Hepatocyte growth factor/scatter factor (HGF/SF) also binds ...

The MUC4 gene, which encodes a human epithelial mucin, is expressed in various epithelial tissues, just as well in adult as in poorly differentiated cells in the embryo and fetus. Its N-terminus and central sequences have previously been reported as comprising a 27-residue peptide signal, followed by a large domain varying in length from 3285 to 7285 amino acid residues. The present study establishes the whole coding sequence of MUC4 in which the C-terminus is 1156 amino acid residues long and shares a high degree of similarity with the rat sialomucin complex (SMC). SMC is a heterodimeric glycoprotein complex composed of mucin (ascites sialoglycoprotein 1, ASGP-1) and transmembrane (ASGP-2) subunits. The same organization is found in MUC4, where the presence of a GlyAspProHis proteolytic site may cleave the large precursor into two subunits, MUC4alpha and MUC4beta. Like ASGP-2, which binds the receptor tyrosine kinase p185(neu), MUC4beta possesses two epidermal growth factor-like domains, a transmembrane sequence and a potential phosphorylated site. MUC4, the human homologue of rat SMC, may be a heterodimeric bifunctional cell-surface glycoprotein of 2.12 micrometers. These results confer a new biological role for MUC4 as a ligand for ErbB2 in cell signalling.