Disease relevance of SDCBP

• Syntenin, a 33 kDa protein, interacts with several cell membrane receptors and with merlin, the product of the causal gene for neurofibromatosis type II [1].
• A recently identified member of this protein family is melanoma differentiation associated gene-9 (mda-9), also known as syntenin, which was first identified as a gene down-regulated during human melanoma differentiation as mda-9 and subsequently recognized as an interacting partner of the cell-surface heparan sulfate syndecans, syntenin [2].
• Interest in mda-9/syntenin is intensifying because of its involvement in organization of protein complexes in the plasma membranes, regulation of B cell development, intracellular trafficking and cell surface targeting, cancer metastasis, synaptic transmission, and axonal outgrowth [2].
• In this review, we discuss the identification, structure and function of mda-9/syntenin and delineate future studies to address its role in regulating key physiological and pathological processes [2].
• Regulating mda-9/syntenin expression using a replication-incompetent adenovirus expressing either sense or antisense mda-9/syntenin modifies the transformed phenotype and alters metastatic ability in immortal human melanocytes and metastatic melanoma cells in vitro and in vivo in newborn rats [3].

High impact information on SDCBP

• Syntenin was found to directly associate with the transcription factor Sox4 [4].
• PIP(2)-PDZ domain binding controls the association of syntenin with the plasma membrane [5].
• We report that most PDZ proteins bind weakly to PIP2, but that syntenin-2, the closest homolog of syntenin-1, binds with high affinity to PIP2 via its PDZ domains [6].
• Syntenin, a PDZ protein that binds syndecan cytoplasmic domains [7].
• Cells that overexpress eGFP-syntenin show numerous cell surface extensions, suggesting effects of syntenin on cytoskeleton-membrane organization [7].

Chemical compound and disease context of SDCBP

• AIMS: To evaluate a digoxigenin-labelled trivalent DNA probe (LT, ST1a, ST1b) for detecting enterotoxigenic Escherichia coli (ETEC), by comparison with a cell culture assay for detecting LT, individual DNA probes for LT, ST1a and ST1b, and an enzyme immunoassay for detecting ST1 [8].

Biological context of SDCBP

• This protein, syntenin, contains a tandem repeat of PDZ domains that reacts with the FYA C-terminal amino acid sequence of the syndecans [7].
• By inference, these data suggest a model whereby recruitment of syntenin to membrane surfaces requires two compatible types of bait that are in "synteny" (occurring together in location) and engages both PDZ domains of syntenin [9].
• Isothermal calorimetric titration of syntenin with syndecan peptide reveals the presence of two binding sites in syntenin [9].
• This study provides the first direct link between mda-9/syntenin expression and tumor cell dissemination in vivo and indicates that mda-9/syntenin expression activates specific signal transduction pathways, which may regulate melanoma tumor progression [3].
• A direct relationship is observed between mda-9/syntenin expression and increased phosphorylation of focal adhesion kinase, c-Jun-NH2-kinase, and p38 [3].

Anatomical context of SDCBP

• Recombinant domains of syntenin with the highest plasma membrane localization display the lowest nuclear localization [10].
• Syntenin is an adapter protein that couples transmembrane proteoglycans to cytoskeletal components and is involved in intracellular vesicle transport [11].
• The addition of a segment of 10 amino acids from the N-terminal domain of syntenin to these PDZ domains increases the localization of the tags to stress fibers and induces the formation of long, branching plasma membrane extensions [10].
• Fibroblast cells expressing heterologous antisense syntenin display alterations in the subcellular distribution of sch-1 [11].
• Lastly, syntenin and ephrin B1 could be co-immunoprecipitated from transfected COS-1 cells, suggesting that PDZ domain binding of B ephrins can occur in cells [12].

Associations of SDCBP with chemical compounds

• PDZ2 mutations have more pronounced effects on binding than PDZ1 mutations, but complete abrogation of syntenin-syndecan binding requires the combination of both the lysine and the alphaB1 mutations in both the PDZ domains of syntenin [9].
• Using sequence homology searches, yeast two-hybrid assays and glutathione S-transferase (GST)-pull-down approaches we have identified a series of glutamate receptor subunits that interact differentially with the PDZ proteins GRIP, PICK1, and syntenin [13].
• PDZ domains in the adaptor protein syntenin interact with syndecans and with the phosphoinositide PIP(2), which is involved in the regulation of the actin cytoskeleton and membrane trafficking [14].
• Recently, we showed that the PDZ domains of syntenin-1 also interact with phosphatidylinositol 4,5-bisphosphate (PIP2) and that this interaction controls the recruitment of the protein to the plasma membrane [6].
• The tyrosine kinase inhibitor CGP 57148 (ST1 571) induces apoptosis in BCR-ABL-positive cells by down-regulating BCL-X [15].

Physical interactions of SDCBP

• Here we provide evidence that each PDZ domain of syntenin can interact with a syndecan [9].
• The paired, but not the isolated PDZ domains of syntenin bind also strongly to the immobilized cytoplasmic domains of neurexin and B-class ephrins [9].
• In addition, the C terminus of syntenin-1 has a stabilizing role in the CD63-syntenin-1 association, as deletion of the last 17 amino acids abolished the interaction [16].

Other interactions of SDCBP

• Our results demonstrated that eIF5A and syntenin could engage in a specific interaction both in vitro and in vivo and functioned collaboratively to regulate p53 activity [17].
• In vitro studies demonstrated that the fifth PDZ domain of FAP-1 and full-length syntenin bound ephrin B1 via the carboxyl-terminal motif [12].
• mda-9/syntenin: recent insights into a novel cell signaling and metastasis-associated gene [2].
• These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component, the proteolytic enzyme cathepsin D and the growth fraction of the tumour, and that it could be a potential new prognostic marker in breast cancer [18].
• Crystal structures of the PDZ2 domain of the scaffolding protein syntenin, both unbound and in complexes with peptides derived from C termini of IL5 receptor (alpha chain) and syndecan, reveal the molecular roots of syntenin's degenerate specificity [19].

Analytical, diagnostic and therapeutic context of SDCBP

• Isolated or combined mutations of the carboxylate binding lysines in the inter-betaAbetaB loops and of the alphaB1 residues in either one or both the PDZ domains of syntenin all reduce syntenin-syndecan binding in yeast two-hybrid, blot-overlay, and surface plasmon resonance assays [9].
• The PDZ2 domain of syntenin at ultra-high resolution: bridging the gap between macromolecular and small molecule crystallography [20].
• In addition to melanoma, gastric cancer tissues exhibited a higher syntenin mRNA expression on a matched tumour/normal cDNA array than their normal counterparts which was statistically significant [21].
• Stromelysin-1 (ST1) was observed in about 10% of epithelial cells in the control groups (cases of fibrocystic and benign proliferative breast disease), while expression (> 10% of expression) was detected in 89.7% of tumours [18].
• Upon immunohistochemistry, the syntenin protein expression was detected in the cytoplasm of primary cutaneous melanomas and melanoma metastases [21].

References