SDC1 (syndecan 1)

2008-03-01   Anurag Purushothaman , Ralph D Sanderson 

Dept. of Pathology, University of Alabama at Birmingham, 814 SHEL, 1530 Third Ave. S., Birmingham, AL 35294, USA

Identity

HGNC
LOCATION
2p24.1
LOCUSID
ALIAS
CD138,SDC,SYND1,syndecan
FUSION GENES

DNA/RNA

Atlas Image
Genomic structure of the two alternative transcript variants of SDC1. Black boxes indicate exons and red boxes indicate untranslated exons.

Description

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.

Transcription

While several transcript variants may exist for this gene, the full-length natures 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.

Pseudogene

None

Proteins

Atlas Image
Schematic representation of the core protein structure of SDC1. C1 and C2 represent highly conserved regions and V represents the central variable region. Lines at amino acids 37, 45 and 47 represents heparan sulfate chain attachment sites and lines at amino acids 210 and 220 represents chondroitin sulfate chain attachment sites.

Description

310 amino acids; 32477 Da; charge -19.5; isoelectric point 4.2618.
The core protein contains 3 domains, an 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 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 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 critical role in lamellipodial spreading, actin bundling and cell migration.

Expression

SDC1 is expressed predominantly on epithelial cells but is also found on distinct stages of differentiation of normal lymphoid cells (pre-B), mesenchymal cells during development and in mature plasma cells.

Localisation

Membrane; Single-pass type I membrane protein.

Function

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 behaviors important in normal and pathological processes. For example, it can function as trans HIV receptors via binding of HIV-1 gp120 to the syndecan heparan sulfate chains and also serves as a primary receptor for natural HPV infection of keratinocytes. SDC1 is required for Wnt-1 - induced mammary tumorigenesis and can function as either tumor suppressor or tumor promoter depending on tumor type and specific location of the proteoglycan (either cell surface or shed into the microenvironment). Core proteins also have functions independent 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. It was recently demonstrated that a domain within the syndecan-1 core protein is required for activation of alphaV/beta3 and alphaV/beta5 integrins and mutational analysis of SDC1 has identified a stretch of 5 hydrophobic amino acids, AVAAV (amino acids 222-226), which are critical for the SDC1 mediated inhibition of tumor cell invasion.

Homology

Belongs to the syndecan family; four members, syndecan- 1, syndecan-2, syndecan-3 and syndecan-4 , have been identified in mammalians. SDC1 orthologs are 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 show 70% sequence identity while the transmembrane domain and cytoplasmic domain show 96 % and 100% identity respectively (see MapViewer).

Mutations

Note

No mutations in the SDC1 gene have been reported.

Implicated in

Note
Syndecan-1 (CD138) is the dominant heparan sulfate proteoglycan expressed on the surface of myeloma cells both in bone marrow and in peripheral blood, and is used as a standard marker by many labs for identification and purification of myeloma cells. On normal cells, syndecan-1 is not expressed on mature B lymphocytes but becomes present at the onset of plasma cell differentiation.
Disease
Myeloma resides predominantly within the bone and is marked by fatigue, intractable bone pain, renal failure and recurrent infections. These effects result from high tumor burden with accompanying cytokine dysregulation, osteolytic bone disease and from the deposition in some patients of high levels of immunoglobulin light chain. 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 tumor growth and metastasis.
Prognosis
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 had a median survival of 20 months, whereas those with a low serum SDC1 had a median survival of 44 months.
Entity name
Haematological malignancies
Note
SDC1 (CD138) is detectable on B-cell chronic lymphocytic leukemia (B-CLL) cells, acute lymphoblastic leukemia (ALL) cells and acute myeloblastic leukemia (AML) cells.
Disease
The serum levels of syndecan-1 were elevated in patients with B-cell chronic lymphocytic leukemia (CLL) and Hodgkin disease (HL).
Prognosis
Serum CD138 level is higher in early stage B-CLL patients than in healthy controls, correlates negatively with peripheral blood lymphocyte count, and is higher in patients with more indolent disease course. Serum CD138 levels increase in early stage B-CLL patients and may have a positive prognostic value as to the dynamics of the disease. The serum levels of syndecan-1 were elevated in patients with HL but did not correlate with markers of tumor burden and prognosis, including serum interleukin-10 and soluble CD30.
Entity name
Breast tumors
Note
Syndecan-1 is expressed at high levels in a significant percentage of breast carcinomas and is related to an aggressive phenotype and poor prognosis. High syndecan-1 expression contributes to the identification of a patient population at particularly high risk of relapse and death.
Disease
High syndecan-1 expression in breast tumors is associated with an aggressive phenotype characterized by larger tumor size, higher tumor grade, higher mitotic count, negative steroid status, and over expression of c-erbB-2 and p53.
Prognosis
In breast cancer, increased expression of SDC1 correlates with an unfavorable prognosis and poor response to chemotherapy.
Entity name
Pancreatic cancer
Note
Syndecan-1 is upregulated in the stroma of pancreatic cancer. Pancreatic cancer tissues express significantly higher levels of syndecan-1 mRNA and protein. SDC1 over expression is an early event in pancreatic carcinogenesis.
Disease
Carcinoma of the pancreas is the 4th leading cause of cancer death in Western countries, with a very short patient survival after diagnosis. Pancreatic cancers over-express a variety of mitogenic growth factors and their receptors and they exhibit tumor-suppressor gene mutations such as p53, p16 and Smad4 and proto-oncogene mutations such as k-ras.
Prognosis
Patients with stromal syndecan-1-positive pancreatic cancer had a worse outcome than patients with stromal syndecan-1 negative tumors. Stromal expression of syndecan-1 seems to be an independent prognostic factor in pancreatic cancer.
Entity name
Gastric cancer
Note
Stromal syndecan-1 expression correlates with deep tumor penetration and larger tumor size. Positive stromal syndecan-1 immunoreactivity correlated with decreased epithelial syndecan-1 expression.
Disease
Risk factors for gastric cancer include: Helicobacter pylori gastric infection, advanced age, male gender, diet including dry salted foods, atrophic gastritis, pernicious anemia, cigarette smoking, Menetriers disease, and familial polyposis. The prognosis of patients with gastric cancer is related to tumor extent and includes both nodal involvement and direct tumor extension beyond the gastric wall.
Prognosis
High expression of syndecan-1 in the stroma in gastric carcinoma is a tumor characteristic associated with a poor prognosis independent of tumor size. Patients with low epithelial syndecan-1 expression in cancer cells had worse overall survival than patients with strong epithelial syndecan-1 staining. Stromal syndecan-1-positive patients had a worse outcome than patients with syndecan-1 negative stroma.
Entity name
Prostrate cancer
Note
Expression of syndecan-1 is associated with established features of biologically aggressive prostate cancer including high PSA levels and lymph node metastases.
Disease
Prostate cancer is the most common noncutaneous malignancy affecting males in the USA. The disease course is variable and about a third of patients eventually fail treatment, as evidenced by a detectable and rising PSA levels.
Prognosis
Patients with features of aggressive progression were more likely to exhibit increased syndecan-1 expression compared with those with features of non aggressive progression.
Entity name
Endometrial Cancer
Note
Stromal syndecan-1 expression is elevated in high-grade endometrial cancer.
Disease
Endometrial cancer is the most common disease among gynecological malignancies and remains a major health concern worldwide.
Prognosis
Loss of epithelial syndecan-1 expression and induction of stromal syndecan-1 expression are associated with reduced survival outcomes in patients with endometrial cancer. Stromal syndecan-1 expression serves as an indicator of poor prognosis in patients with endometrial cancer.
Entity name
Ovary carcinoma
Note
Syndecan-1 is present in the epithelial cells, cancer cells, and stromal cells of benign, borderline, and malignant ovarian tumor sections. Stromal syndecan-1 expression is observed in the most invasive areas of ovarian cancer.
Disease
Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies. The most important risk factor for ovarian cancer is a family history of a first-degree relative (mother, daughter, or sister) with the disease.
Prognosis
Stromal syndecan-1 expression is associated with decreased survival in patients with ovarian carcinoma.
Entity name
Lung cancers
Note
Serum syndecan-1 is a powerful prognostic factor in lung cancer. Lung cancer patients have high serum syndecan 1. High levels of circulating syndecan-1 also in part reflect the presence of a large tumor mass and are associated with advanced cancer.
Disease
Lung cancers are neuroendocrine lung tumors (small cell lung carcinomas, carcinoids, large cell neuroendocrine carcinomas) or non neuroendocrine lung tumors (squamous carcinomas, adenocarcinomas, large cell carcinomas).
Prognosis
High serum syndecan-1 levels at diagnosis are associated with an advanced stage and poor outcome in lung cancer.

Bibliography

Pubmed IDLast YearTitleAuthors
21731541990Localization of gene for human syndecan, an integral membrane proteoglycan and a matrix receptor, to chromosome 2.Ala-Kapee M et al
108888842000Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice.Alexander CM et al
126602312003Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor.Anisfeld AM et al
128794632003High syndecan-1 expression in breast carcinoma is related to an aggressive phenotype and to poorer prognosis.Barbareschi M et al
127498512003Syndecan-1-mediated cell spreading requires signaling by alphavbeta3 integrins in human breast carcinoma cells.Beauvais DM et al
108724651999Functions of cell surface heparan sulfate proteoglycans.Bernfield M et al
86629791996The cytoplasmic domain of syndecan-1 is required for cytoskeleton association but not detergent insolubility. Identification of essential cytoplasmic domain residues.Carey DJ et al
159301352005Functional role of syndecan-1 cytoplasmic V region in lamellipodial spreading, actin bundling, and cell migration.Chakravarti R et al
103503301999Syndecan-1 (CD 138) in myeloma and lymphoid malignancies: a multifunctional regulator of cell behavior within the tumor microenvironment.Dhodapkar MV et al
158513812005Prognostic significance of syndecan-1 expression in human endometrial cancer.Hasengaowa et al
158865012005Syndecan-1 expression--a novel prognostic marker in pancreatic cancer.Juuti A et al
90509111997The mapping and visual ordering of the human syndecan-1 and N-myc genes near the telomeric region of chromosome 2p.Kaukonen J et al
155634542005Identification of an invasion regulatory domain within the core protein of syndecan-1.Langford JK et al
13394311992Differential expression of cell surface heparan sulfate proteoglycans in human mammary epithelial cells and lung fibroblasts.Lories V et al
147447762004Induction of syndecan-1 expression in stromal fibroblasts promotes proliferation of human breast cancer cells.Maeda T et al
23241021990Sequence of human syndecan indicates a novel gene family of integral membrane proteoglycans.Mali M et al
151774972004Shift of syndecan-1 expression from epithelial to stromal cells during progression of solid tumours.Mennerich D et al
168401942006Serum levels of syndecan-1 in B-cell chronic lymphocytic leukemia: correlation with the extent of angiogenesis and disease-progression risk in early disease.Molica S et al
174139802007Expression of extracellular matrix proteins in ovarian serous tumors.Salani R et al
180270902008Syndecan-1: a dynamic regulator of the myeloma microenvironment.Sanderson RD et al
146455692003Different heparan sulfate proteoglycans serve as cellular receptors for human papillomaviruses.Shafti-Keramat S et al
178684222008Prognostic value of syndecan-1 expression in patients treated with radical prostatectomy.Shariat SF et al
120913552002Soluble syndecan-1 promotes growth of myeloma tumors in vivo.Yang Y et al

Other Information

Locus ID:

NCBI: 6382
MIM: 186355
HGNC: 10658
Ensembl: ENSG00000115884

Variants:

dbSNP: 6382
ClinVar: 6382
TCGA: ENSG00000115884
COSMIC: SDC1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000115884ENST00000254351P18827
ENSG00000115884ENST00000381150P18827
ENSG00000115884ENST00000403076E9PHH3
ENSG00000115884ENST00000429035H7C1K4
ENSG00000115884ENST00000447124F8WCX9

Expression (GTEx)

0
100
200
300
400
500
600
700

Pathways

PathwaySourceExternal ID
ECM-receptor interactionKEGGko04512
Cell adhesion molecules (CAMs)KEGGko04514
ECM-receptor interactionKEGGhsa04512
Cell adhesion molecules (CAMs)KEGGhsa04514
MalariaKEGGko05144
MalariaKEGGhsa05144
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
DiseaseREACTOMER-HSA-1643685
Diseases of glycosylationREACTOMER-HSA-3781865
Diseases associated with glycosaminoglycan metabolismREACTOMER-HSA-3560782
Defective B4GALT7 causes EDS, progeroid typeREACTOMER-HSA-3560783
Defective B3GAT3 causes JDSSDHDREACTOMER-HSA-3560801
Defective EXT1 causes exostoses 1, TRPS2 and CHDSREACTOMER-HSA-3656253
Defective EXT2 causes exostoses 2REACTOMER-HSA-3656237
HemostasisREACTOMER-HSA-109582
Cell surface interactions at the vascular wallREACTOMER-HSA-202733
Signal TransductionREACTOMER-HSA-162582
Visual phototransductionREACTOMER-HSA-2187338
Retinoid metabolism and transportREACTOMER-HSA-975634
MetabolismREACTOMER-HSA-1430728
Metabolism of carbohydratesREACTOMER-HSA-71387
Glycosaminoglycan metabolismREACTOMER-HSA-1630316
Heparan sulfate/heparin (HS-GAG) metabolismREACTOMER-HSA-1638091
A tetrasaccharide linker sequence is required for GAG synthesisREACTOMER-HSA-1971475
HS-GAG biosynthesisREACTOMER-HSA-2022928
HS-GAG degradationREACTOMER-HSA-2024096
Chondroitin sulfate/dermatan sulfate metabolismREACTOMER-HSA-1793185
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Extracellular matrix organizationREACTOMER-HSA-1474244
Non-integrin membrane-ECM interactionsREACTOMER-HSA-3000171
Syndecan interactionsREACTOMER-HSA-3000170
Defective B3GALT6 causes EDSP2 and SEMDJL1REACTOMER-HSA-4420332
Metabolism of fat-soluble vitaminsREACTOMER-HSA-6806667
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
129042962003Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration.108
217721252011A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients.107
200978822010Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis.99
192551472009Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor.95
154797432004The syndecan-1 ectodomain regulates alphavbeta3 integrin activity in human mammary carcinoma cells.93
146455692003Different heparan sulfate proteoglycans serve as cellular receptors for human papillomaviruses.89
191072062008Distinct genetic loci control plasma HIV-RNA and cellular HIV-DNA levels in HIV-1 infection: the ANRS Genome Wide Association 01 study.82
212577202011SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis.80
173394232007Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma.72
200810592010Circulating human B and plasma cells. Age-associated changes in counts and detailed characterization of circulating normal CD138- and CD138+ plasma cells.71

Citation

Anurag Purushothaman ; Ralph D Sanderson

SDC1 (syndecan 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-03-01

Online version: http://atlasgeneticsoncology.org/gene/42223/sdc1-(syndecan-1)