The syndecans are transmembrane proteoglycans that place structurally heterogeneous heparan sulfate chains at the cell surface and a highly conserved polypeptide in the cytoplasm. Their versatile heparan sulfate moieties support various processes of molecular recognition, signaling, and trafficking. Here we report the identification of a protein that binds to the cytoplasmic domains of the syndecans in yeast two-hybrid screens, surface plasmon resonance experiments, and ligand-overlay assays. This protein, syntenin, contains a tandem repeat of PDZ domains that reacts with the FYA C-terminal amino acid sequence of the syndecans. Recombinant enhanced green f luorescent protein (eGFP)-syntenin fusion proteins decorate the plasmamembrane and intracellular vesicles, where they colocalize and cosegregate with syndecans. Cells that overexpress eGFP-syntenin show numerous cell surface extensions, suggesting effects of syntenin on cytoskeleton-membrane organization. We propose that syntenin may function as an adaptor that couples syndecans to cytoskeletal proteins or cytosolic downstream signaleffectors.The cell surface heparan sulfate proteoglycans are at the cross-section of several different pathways (1, 2). The heparan sulfate moieties of these molecules bind various differentiation, growth, and scatter factors, facilitate the occupation and activation of the corresponding signal-transducing receptors, and are involved in the internalization and clearance of the signaling complexes from the cell surface (3). They assist receptors that are involved in cell-cell (4) and cell-matrix (5) adhesion and assist scavenging receptors that are involved in the endocytosis and transcytosis of lipoproteins and lipases (6). They also bind and activate serine proteinase inhibitors and accelerate the reactions of these inhibitors with their targets (7). Proteolysis, lipolysis, mesoderm induction, gastrulation, angiogenesis, and neuritogenesis all appear to be regulated by or to depend on heparan sulfate because this glycosaminoglycan is needed for the allosteric activation, approximation, and compartmentalization of the reactants that are engaged in these processes.In most cells syndecans represent the major source of cell surface heparan sulfate. The four known vertebrate syndecans are small type I membrane proteins, with similar and simple domain organizations: a single ectodomain, membrane span, and cytoplasmic domain (1). The ectodomains of the different syndecans have little in common, except for the presence of three or four consensus sites for heparan sulfate attachment near the N termini of the proteins and a dibasic, presumably protease-sensitive site at the junction with the membrane spanning segment. The structures of these ectodomains have not been evolutionary conserved, except again for these shared structural elements. The membrane-spanning and the small cytoplasmic domains of the syndecans, in contrast, show extensive structural similarity (Ϸ60% sequence identity) and have been highly conserved during evolutio...
