Transmembrane Signaling Proteoglycans

Abstract

Virtually all metazoan cells contain at least one and usually several types of transmembrane proteoglycans. These are varied in protein structure and type of polysaccharide, but the total number of vertebrate genes encoding transmembrane proteoglycan core proteins is less than 10. Some core proteins, including those of the syndecans, always possess covalently coupled glycosaminoglycans; others do not. Syndecan has a long evolutionary history, as it is present in invertebrates, but many other transmembrane proteoglycans are vertebrate inventions. The variety of proteins and their glycosaminoglycan chains is matched by diverse functions. However, all assume roles as coreceptors, often working alongside high-affinity growth factor receptors or adhesion receptors such as integrins. Other common themes are an ability to signal through their cytoplasmic domains, often to the actin cytoskeleton, and linkage to PDZ protein networks. Many transmembrane proteoglycans associate on the cell surface with metzincin proteases and can be shed by them. Work with model systems in vivo and in vitro reveals roles in growth, adhesion, migration, and metabolism. Furthermore, a wide range of phenotypes for the core proteins has been obtained in mouse knockout experiments. Here some of the latest developments in the field are examined in hopes of stimulating further interest in this fascinating group of molecules.

Metastasis Suppressor Tetraspanin CD82/KAI1 Regulates Ubiquitylation of Epidermal Growth Factor Receptor

“…Therefore, one can envisage a scenario whereby CD82 and its tetraspanin partners (e.g., CD9, which is known to associate with syndecans (3,5)) facilitate formation of the tripartite EGFR-growth factor-HSPG complex, which activates not only receptor but also HSPG. CD82 and activated HSPG (e.g., syndecans) could, in turn, recruit PKC␣ (40,41), thereby increasing effective concentration of the enzyme in proximity to its targets (i.e., EGFR, c-Cbl). Consequently, increased phosphorylation of threonine 654 in EGFR on one hand and serine phosphorylation of c-Cbl on the other would lead to changes in both ligand-induced ubiquitylation of the receptor and alteration of its postendocytic trafficking route (33) (Fig.…”

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

“…1A). 93,94 All cells express syndecans on their surface, 95 and all four syndecans are expressed in the heart. 96 Syndecans interact with a wide range of molecules, including growth factors, ECM proteins, cytokines and pathogens through their GAG chains, thereby regulating biological processes spanning from proliferation and differentiation to wound healing and inflammation.…”

Regulation of Xylosyltransferase I Gene Expression by Interleukin 1β in Human Primary Chondrocyte Cells

“…They are characterized by the presence of one or multiple glycosaminoglycan (GAG) side chains covalently linked to a core protein. The ability of GAGs to bind a wide range of ligands such as cytokines, chemokines, growth factors, and enzymes confer to PGs a critical role in the regulatory network of the cell (1). Thus, PGs are implicated in various physiological functions, including cell signaling and morphogenesis, cell proliferation, normal development, cellular cross-talk, and organization of the extracellular matrix (2)(3)(4).…”