DEFINITION
Syndecan-1 (CD138) is a member of the proteoglycan family, syndecan, composed with 4 members. All syndecans are transmembrane heparin sulfate proteoglycan with an N-terminal signal peptide, an ectodomain, a single hydrophobic transmembrane domain and a short C-terminal cytoplasmic domain.
The syndecan-1 protein functions as an integral membrane protein and participates in:
- Cell migration;
- Cell signaling;
- Cytoskeletal organization and mediates both cell-cell and cell-extracellular matrix interactions.
SDC1 is expressed predominantly on epithelial cells, but it is also found on distinct stages of differentiation of normal lymphoid cells (pre-B), mesenchymal cells during development and in mature plasma cells.
THE GENE
Human syndecan-1 gene located to 2p23-24, just centromeric to the N-myc gene at 2p24.1.
The SDC1 gene contains 9 exons and spans 24,6366 bases (start 20,264,039 bp from pter to end 20,288,675) oriented at the minus strand.
While several transcript variants may exist for this gene, the full-length nature of only two have been described to date. These two represent the major variants of this gene and encode the same protein.
Variant 1 (NM_001006946) represents the longer transcript and variant 2 (NM_002997) differs in the 5' UTR compared to variant 1.
Variant 1: exons-6; transcript length-3309 bp and translation length -310 residues.
Variant 2: exons-5; transcript length-3217 bp and translation length -310 residues.
Pseudogenes don’t exist.
Official Symbol: SDC1
Other Designations: CD138, SDC, SYND1
Location: 2p24.1
CHEMICAL STRUCTURE AND IMAGES
The cDNA encodes a core protein of 310 amino acids. CD138 protein is a single chain molecule of 30.5 KDa with isoelectric point 4.2618.
The core protein contains 3 domains: ectodomain (extracellular domain), transmembrane domain and cytoplasmic domain.
The ectodomain contains a cleavable amino terminal single peptide and the glycosaminoglycan attachment sites. There are 3 highly conserved serine-glycine sites for heparan sulfate attachment (amino acids 37,45 and 47) near the N-terminal of the core protein and there are 2 highly conserved serine-glycine sites for chondroitin sulfate attachment ( amino acids 210 and 220), adjacent to the cell membrane.
Shedding of the ectodomain occurs via protease sensitive sites near the plasma membrane.
The transmembrane domain, which is highly conserved among the syndecan family members, contains an unusual motif of glycine/alanine that aligns on one face of the domain in the outer membrane leaflet. The non-catalytic COOH-terminal, cytoplasmic domain, which is relatively short (30 amino acids), contains 2 highly conserved regions (C1 and C2) which are identical in each of the 4 syndecan family members (the exception being a conservative substitution of arginine for lysine in syndecan 2). These flank is a central variable region (V) that is distant for each family member. The sequence for variable domain (V) for SDC1 is SLEEPKQANGGAYQKPTKQE. The cytoplasmic domain of SDC1 is required for linking the molecule to the cytoskeleton and this interaction is dependent on a tyrosine residue that is conserved among all known syndecan family sequences. The cytoplasmic V region plays a critical role in lamellipodial spreading, actin bundling and cell migration.
Tertiary structure:
Protein Aminoacids Percentage
SDC1 orthologs have been found in mouse, rat, dog, chimpanzee, guinea pig, chinese hamster, hedgehog, cat, pika, platypus, bushbaby, tree shrew, and chicken. The extracellular domains of human and mouse SDC1 shows 70% sequence identity, while the transmembrane domain and cytoplasmic domain shows 96% and 100% identity respectively.
SYNTHESIS AND TURNOVER
SDC1 is expressed predominantly on epithelial cells, but it is also found on distinct stages of differentiation of normal lymphoid cells (pre-B), mesenchymal cells during development and in mature plasma cells. Syndecan-1 localization is not restricted to the cell surface: it is present in the nucleus, where it regulates gene transcription, or it can be shed from the cell surface and become a soluble or insoluble component of the extracellular matrix. Although progress has been made toward elucidating the structures and activities of syndecans, the exact mechanisms controlling the expression of these molecules are not known. You know that syndecan-1 mRNA expression results from the antagonistic effects of increased intracellular cAMP and intracellular calcium levels and that different cell types regulate the expression and post-translational modifications of syndecan-1 in response to growth factors and cytokines in different manners. (Post-transcriptional Regulation of Syndecan-1 Expression by cAMP in Peritoneal Macrophages, 1993).
It was demonstrated that the physiological degradation of syndecan-1 gives rise to active metabolites and that heparanase (HPSE-1) is one of the enzymes know involved in the degradation of syndecan-1 (Heparanase Degrades Syndecan-1 and Perlecan Heparan Sulfate, 2003).
CELLULAR FUNCTIONS
The syndecan-1 proteoglycan regulates cell proliferation, cell migration, cell signaling, cytoskeletal organization and mediates both cell-cell and cell-extracellular matrix interactions. Additionally, via its heparan sulfate chains, it binds a wide range of bioactive molecules (e.g., growth factors, chemokines) that regulate cell behaviours important in normal and pathological processes.(Sdc1 negatively modulates carcinoma cell motility and invasion, 2010).
Core proteins also have independent functions of the heparan sulfate chains. The cytoplasmic domains can transmit signals and they also bind to anchoring molecules including PDZ family members. The extracellular domains bear the attached heparan sulfate chains but also interact with, and regulate, other cell adhesion molecules and cell surface receptors independent of their heparan sulfate chains.
The role of syndecans in adhesion is complicated by their interactions with other adhesion receptors. Syndecans are signalling co-receptors that are able to regulate cell adhesion to the ECM in collaboration with the associated family of integrin receptors. It, along with integrins, binds to the ECM and modulate Rho family members that control the activation of focal adhesion kinase (FAK) at focal adhesions: it is a co-receptor for type I collagen and cooperates with integrin α2β1.
The membrane-proximal domain C1 contains a cationic sequence, common to many transmembrane molecules, there are interactions with Ezrin, an actinassociated cytoskeletal protein.
Moreover, syndecan-1 is able to interact with pro-angiogenic factors such as vascular endothelial
growth factor (VEGF) and basic fibroblastic growth factor. Syndecan-1 seems to be able to modulate neovascularisation by increasing the local concentration of growth factors, by mediating their binding to specific receptors and/or by interacting directly with the receptors.
DIAGNOSTIC USE
Syndecan-1 binds to many mediators of disease pathogenesis. Through these molecular interactions, it can modulate leukocyte recruitment, cancer cell proliferation and invasion, angiogenesis, microbial attachment and entry, host defence mechanisms, and matrix remodelling.
No mutations in the SDC1 gene have been reported, but his expression appears dysregulated in many diseases, like:
- Inflammatory disease: where it has a role in the leukocyte recruitment, resolution of inflammation and matrix remodelling. It attenuates non-infectious inflammatory diseases by inhibiting leukocyte adhesion onto the activated endothelium, reducing the expression and inhibiting the activity of pro-inflammatory factors, confining leukocyte infiltration to specific sites of tissue injury or by removing sequestered chemokines and facilitating the resolution of inflammation.
- Cancer: it enhances oncogene and growth factor signaling, inhibits cancer cell apoptosis, and promotes angiogenesis.
- Infectious disease: syndecan-1 clearly promotes pathogenesis as it mediates the attachment and entry of pathogens into host.
The data suggests that one of the crucial functions of mammalian syndecan-1 in vivo is to assure the adequate and correct functioning of inflammation. (Molecular functions of syndecan-1 in disease, 2011)
The most important type of cancers in which SDC1 is implicated and in which it is used as a prognostic factor are:
- Multiple Myelomas: cell surface SDC1 mediates adhesion of myeloma cells to collagen, inhibits invasion through collagen gels and also can mediate myeloma cell-cell adhesion. In contrast, shed syndecan-1 actively promotes myeloma tumour growth and metastasis. Shedding of syndecan-1 from the myeloma cell surface occurs actively via proteolytic sheddases and a high level of syndecan-1 in the serum is an independent predictor of poor prognosis in myeloma. Patients with high serum SDC1 have a median survival of 20 months, whereas those with a low serum SDC1 have a median survival of 44 months. (Syndecan-1 promotes the angiogenic phenotype of multiple myeloma endothelial cells, 2011).
- Haematological malignancies: SDC1 is detectable on B-cell chronic lymphocytic leukemia (B-CLL) cells, acute lymphoblastic leukemia (ALL) cells and acute myeloblastic leukemia (AML) cells. High level of serum CD138 may have a positive prognostic value in B-CLL patients.
- Breast tumours: high syndecan-1 expression in breast tumours is associated with an aggressive phenotype, characterized by larger tumour size, higher tumour grade, higher mitotic count, negative steroid status, and over expression of c-erbB-2 and p53.
- Pancreatic cancer: patients with stromal syndecan-1-positive pancreatic cancer have a worse outcome than patients with stromal syndecan-1 negative tumours. Stromal expression of syndecan-1 seems to be an independent prognostic factor in pancreatic cancer.
- Gastric cancer: patients with low epithelial syndecan-1 expression in cancer cells have worse overall survival than patients with strong epithelial syndecan-1 staining. Stromal syndecan-1-positive patients have a worse outcome than patients with syndecan-1 negative stroma.
- Prostrate cancer: expression of syndecan-1 is associated with established features of biologically aggressive prostate cancer including high PSA levels and lymph node metastases.
- Endometrial cancer: stromal syndecan-1 expression is elevated in high-grade endometrial cancer.
- Ovary carcinoma: stromal syndecan-1 expression is observed in the most invasive areas of ovarian cancer.
- Lung cancers: high levels of circulating syndecan-1 also in part reflect the presence of a large tumour mass and are associated with advanced cancer.
THERAPEUTIC USE
Hiroshi Ikeda et al. investigated the antitumour effect of murine/human chimeric CD138-specific monoclonal antibody nBT062 conjugated with highly cytotoxic maytansinoid derivatives against multiple myeloma (MM) cells in vitro and in vivo.
Anti-CD138 immunoconjugates significantly inhibited growth of MM cell lines and primary tumor cells from MM patients without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G2-M cell cycle arrest, followed by apoptosis associated with cleavage of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase. Nonconjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that specific binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells. The co-culture of MM cells with bone marrow stromal cells protects against dexamethasone-induced death but had no effect on the cytotoxicity immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumour growth in vivo and prolonged host survival in both the xenograft mouse models of human MM and SCID mouse model. (The Monoclonal Antibody nBT062 Conjugated to Cytotoxic Maytansinoids Has Selective Cytotoxicity Against CD138-Positive Multiple Myeloma Cells In vitro and In vivo, 2009)
Petiti Jessica
Barbarossa Luigi
