Syntenin, a PDZ protein that binds syndecan cytoplasmic domains

Abstract

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...

Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output

“…Since then, it has been shown to regulate the metastatic phenotype of human melanoma cells through interactions with c-src, protein kinase C alpha and activation of nuclear factor-kB and p38 signaling pathways (Boukerche et al, , 2010Sarkar et al, 2008). Syntenin also bind and regulate syndecans as co-receptors for various growth factors and matrix components, thereby controlling cellular proliferation, differentiation, adhesion and migration (Grootjans et al, 1997;Lambaerts et al, 2009). The adapter molecule syntenin may provide crosstalk between these pathways and Sox4 that may be important for regulating the tumorigenic properties of transformed cells.…”

Syndecan-1 and syndecan-4 can mediate the invasion of OpaHSPG-expressing Neisseria gonorrhoeae into epithelial cells

“…We therefore conclude that the absence of the intracellular domain of either syndecan has a dominantnegative effect on bacterial uptake, probably by preventing a necessary tight interaction of the endogenous syndecans with signalling molecules or the cytoskeleton. It has been shown that the last four amino acids of the intracellular domain of all syndecans are strictly conserved (amino acids EFYA) and are responsible for mediating interaction with several proteins containing PDZ domains (Grootjans et al, 1997;Cohen et al, 1998;Hsueh et al, 1998). One of these proteins, CASK, binds to protein 4.1, thereby connecting the complex to the actin cytoskeleton .…”

“…All syndecans interact physically with cytoskeletal components via their intracellular domain. The C-terminal amino acid motif EFYA in the intracellular domain is involved in binding to syntenin (Grootjans et al, 1997) and other PDZ motif-containing proteins, which are thought to be linked to the actin cytoskeleton via additional protein±protein interactions Hsueh et al, 1998). Furthermore, syndecans are likely to play important roles in signal transduction, as their intracellular domain can be phosphorylated (reviewed by Zimmermann and David, 1999).…”

The Lymphocyte Receptor CD6 Interacts with Syntenin-1, a Scaffolding Protein Containing PDZ Domains

“…Most of the protein interactions reported for syntenin-1 are mediated through its PDZ domains, which bind to short hydrophobic C-terminal amino acid motifs of the target proteins (26). The PDZ domains of syntenin-1 may function in a cooperative fashion and exhibit degenerate specificity because they may bind to several C-terminal peptide sequences (27,41).…”

“…PDZ family proteins are involved in the localization of receptors and cytosolic effectors to specific membrane sites and in linking extracellular signals to the cytoskeleton and intracellular signaling pathways. Syntenin-1 was originally identified as a syndecan-binding PDZ protein (26), and later on has been shown to interact with about one dozen proteins, most of which are membrane receptors (27). Interestingly, syntenin-1 has been found to interact with both preand postsynaptic neuronal receptors (28 -31).…”