Alternative titles; symbols
HGNC Approved Gene Symbol: SDC1
Cytogenetic location: 2p24.1 Genomic coordinates (GRCh38): 2:20,200,797-20,225,475 (from NCBI)
Syndecan, a cell surface proteoglycan, is an integral membrane protein acting as a receptor for the extracellular matrix. It is one of a group of transmembrane heparan sulfate proteoglycans. Homologs of the human syndecan gene have been identified in mouse, rat, and Chinese hamster.
Sanderson et al. (1989) showed that Sdc1 is expressed in mouse only when and where B lymphocytes associate with extracellular matrix, namely as B-cell precursors in bone marrow and as immobilized plasma cells in interstitial matrices. Expression is lost immediately before maturation and release of B lymphocytes into the circulation and is absent on circulating and mature peripheral B lymphocytes. SDC1 is reexpressed on differentiated plasma cells and is a marker for cells secreting immunoglobulin.
By probing a breast epithelial cell line cDNA library with mouse syndecan probes, Mali et al. (1990) obtained a cDNA encoding human SDC1. Sequence analysis predicted that the 310-amino acid human protein is 77% identical to the mouse sequence. SDC1 has an ectodomain, a 25-residue transmembrane domain, and a 34-residue cytoplasmic domain, which are 70%, 96%, and 100% identical to those of the mouse protein, respectively. The ectodomain is preceded by an N-terminal signal peptide and contains 5 potential glycosaminoglycan-attachment sites, 1 potential N-glycosylation site, and a dibasic lys-arg cleavage site adjacent to the transmembrane domain. Northern blot analysis revealed expression of 2.6- and 3.4-kb SDC1 transcripts in mammary epithelial and carcinoma cells and in fetal skin; a 4.5-kb transcript was detected in brain.
For chromosomal localization of the SDC1 gene in the human, Ala-Kapee et al. (1990) analyzed a panel of mouse-human somatic cell hybrids by Southern blotting using a cDNA probe for human syndecan. In this way, they succeeded in assigning the gene to chromosome 2. Westman et al. (1991) showed that the SDC gene is on 2p by the study of somatic cell hybrids carrying various fragments of chromosome 2. Oettinger et al. (1991) mapped the Synd gene to mouse chromosome 12 by a variety of approaches. Southern analysis of mouse-hamster cell hybrid DNA showed a second hybridizing sequence on the X chromosome. Spring et al. (1994) showed that the gene that maps to mouse chromosome 12 and to human chromosome 2 encodes syndecan-1 and is located next to the NMYC gene (164840) which maps to 2p24.1. There is a curious physical relationship between 4 syndecan genes and 4 genes of the MYC family.
Bobardt et al. (2003) demonstrated that syndecans, including SDC1, can function as in trans HIV receptors via binding of HIV-1 gp120 to the syndecan heparan sulfate chains. Flow cytometric analysis demonstrated SDC expression on endothelial cells. HIV bound to SDC on endothelial cell lines maintained its infectivity for at least 1 week, compared with less than 1 day for unbound virus. Bobardt et al. (2003) suggested that SDC-rich endothelial cells lining the vasculature can provide a microenvironment that boosts HIV replication in T cells.
Ma et al. (2006) found that syndecan-1 (SDC1; 186355) was required for lacritin (LACRT; 607360)-dependent mitogenesis and COX2 (PTGS2; 600262) expression. Lacritin targeted and interacted with cell surface SDC1 during an upstream step in lacritin mitogenic signaling. Binding was mediated by the lacritin C-terminal mitogenic domain and the SDC1 N terminus. However, binding of lacritin to SDC1 was independent of SDC1 heparan sulfate (HS) glycosaminoglycan chains, as the lacritin C terminus showed affinity for the SDC1 core protein but not the HS glycosaminoglycan chains. The HS-rich N terminus of SDC1 was partially deglycanated by heparanase-1 (HPSE; 604724), which exposed the SDC1 core protein to facilitate lacritin binding and signaling to mitogenic COX2.
Yao et al. (2019) developed an unbiased functional target discovery platform to query oncogeneic KRAS (190070)-dependent changes of the pancreatic ductal adenocarcinoma (see 260350) surfaceome, which revealed SDC1 as a protein that is upregulated at the cell surface by oncogenic KRAS. Localization of SDC1 at the cell surface, where it regulates macropinocytosis, an essential metabolic pathway that fuels pancreatic ductal adenocarcinoma cell growth, is essential for disease maintenance and progression.
Alexander et al. (2000) examined the role of syndecan-1 during mammary tumor development in mice in response to the ectopic expression of the Wnt1 protooncogene (164820). They crossed syndecan-1-deficient mice with transgenic mice that expressed Wnt1 in mammary gland. Ectopic Wnt1 expression induces generalized mammary hyperplasia, followed by the development of solitary tumors. Alexander et al. (2000) showed that in Sdc1 -/- mice, Wnt1-induced hyperplasia in virgin mammary gland was reduced by 70%, indicating that the Wnt1 signaling pathway was inhibited. In addition, they showed that soluble syndecan-1 ectodomain purified by mouse mammary epithelial cells stimulated the activity of a Wnt1 homolog in a tissue culture assay. The results provided both genetic and biochemical evidence that syndecan-1 can modulate Wnt signaling and is critical for Wnt1-induced tumorigenesis in the mouse mammary gland.
Reizes et al. (2001) found that transgenic expression in the hypothalamus of Sdc1 produced mice with hyperphagia and maturity-onset obesity resembling mice with reduced action of alpha-melanocyte-stimulating hormone (alpha-MSH; see 155555). Via their heparan sulfate chains, syndecans potentiate the action of agouti-related protein (602311) and agouti signaling protein (600201), endogenous inhibitors of alpha-MSH. In wildtype mice, Sdc3 (186357), the predominantly neural syndecan, was expressed in hypothalamic regions that control energy balance. Food deprivation increased hypothalamic Sdc3 levels several-fold. Sdc3 null mice, which otherwise appeared normal, responded to food deprivation with markedly reduced reflex hyperphagia. Reizes et al. (2001) proposed that oscillation of hypothalamic SDC3 levels physiologically modulates feeding behavior.
In matrilysin (MMP7; 178990) null mice, Li et al. (2002) found that neutrophils remained confined in the interstitium of injured lungs and did not advance into the alveolar space. Impaired transepithelial migration was accompanied by a lack of both shed Sdc1 and Cxcl1 (155730) in the alveolar fluid. Cxcl1 was bound to shed Sdc1, and it was not detected in the lavage of Sdc1 null mice. In vitro, Mmp7 cleaved Sdc1 from the surface of cells. The authors concluded that MMP7-mediated shedding of SDC1/CXCL1 complexes from the mucosal surface directs and confines neutrophil influx to sites of injury.
In heparan sulfate- or SDC1-deficient mice and mice with intestinal-specific loss of heparan sulfate, Bode et al. (2008) observed increased basal protein leakage and increased susceptibility to protein loss induced by combinations of IFN-gamma (147570), TNF-alpha (191160), and increased venous pressure. Similarly, knockdown of SDC1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Administration of the nonanticoagulant 2,3-de-O-sulfated heparin prevented intestinal protein leakage in Sdc1-deficient mice.
Ala-Kapee, M., Nevanlinna, H., Mali, M., Jalkanen, M., Schroder, J. Localization of gene for human syndecan, an integral membrane proteoglycan and a matrix receptor, to chromosome 2. Somat. Cell Molec. Genet. 16: 501-505, 1990. [PubMed: 2173154] [Full Text: https://doi.org/10.1007/BF01233200]
Alexander, C. M., Reichsman, F., Hinkes, M. T., Lincecum, J., Becker, K. A., Cumberledge, S., Bernfield, M. Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice. Nature Genet. 25: 329-332, 2000. [PubMed: 10888884] [Full Text: https://doi.org/10.1038/77108]
Bobardt, M. D., Saphire, A. C. S., Hung, H.-C., Yu, X., Van der Schueren, B., Zhang, Z., David, G., Gallay, P. A. Syndecan captures, protects, and transmits HIV to T lymphocytes. Immunity 18: 27-39, 2003. [PubMed: 12530973] [Full Text: https://doi.org/10.1016/s1074-7613(02)00504-6]
Bode, L., Salvestrini, C., Park, P. W., Li, J.-P., Esko, J. D., Yamaguchi, Y., Murch, S., Freeze, H. H. Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function. J. Clin. Invest. 118: 229-238, 2008. [PubMed: 18064305] [Full Text: https://doi.org/10.1172/JCI32335]
Li, Q., Park, P. W., Wilson, C. L., Parks, W. C. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111: 635-646, 2002. [PubMed: 12464176] [Full Text: https://doi.org/10.1016/s0092-8674(02)01079-6]
Ma, P., Beck, S. L., Raab, R. W., McKown, R. L., Coffman, G. L., Utani, A., Chirico, W. J., Rapraeger, A. C., Laurie, G. W. Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin. J. Cell Biol. 174: 1097-1106, 2006. Note: Erratum: J. Cell Biol. 192: 365 only, 2011. [PubMed: 16982797] [Full Text: https://doi.org/10.1083/jcb.200511134]
Mali, M., Jaakkola, P., Arvilommi, A.-M., Jalkanen, M. Sequence of human syndecan indicates a novel gene family of integral membrane proteoglycans. J. Biol. Chem. 265: 6884-6889, 1990. [PubMed: 2324102]
Oettinger, H. F., Streeter, H., Lose, E., Copeland, N. G., Gilbert, D. J., Justice, M. J., Jenkins, N. A., Mohandas, T., Bernfield, M. Chromosome mapping of the murine syndecan gene. Genomics 11: 334-338, 1991. [PubMed: 1769649] [Full Text: https://doi.org/10.1016/0888-7543(91)90140-a]
Reizes, O., Lincecum, J., Wang, Z., Goldberger, O., Huang, L., Kaksonen, M., Ahima, R., Hinkes, M. T., Barsh, G. S., Rauvala, H., Bernfield, M. Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Cell 106: 105-116, 2001. [PubMed: 11461706] [Full Text: https://doi.org/10.1016/s0092-8674(01)00415-9]
Sanderson, R. D., Lalor, P., Bernfield, M. B lymphocytes express and lose syndecan at specific stages of differentiation. Cell Regul. 1: 27-35, 1989. [PubMed: 2519615] [Full Text: https://doi.org/10.1091/mbc.1.1.27]
Spring, J., Goldberger, O. A., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Bernfield, M. Mapping of the syndecan genes in the mouse: linkage with members of the Myc gene family. Genomics 21: 597-601, 1994. [PubMed: 7959737] [Full Text: https://doi.org/10.1006/geno.1994.1319]
Westman, P., Hsieh, C.-L., Mali, M., Jalkanen, M., Francke, U., Schroder, J. Assignment of the human syndecan (SDC) gene to short arm of chromosome 2. (Abstract) Cytogenet. Cell Genet. 58: 1873-1874, 1991.
Yao, W., Rose, J. L., Wang, W., Seth, S., Jiang, H., Taguchi, A., Liu, J., Yan, L., Kapoor, A., Hou, P., Chen, Z., Wang, Q., and 26 others. Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. Nature 568: 410-414, 2019. [PubMed: 30918400] [Full Text: https://doi.org/10.1038/s41586-019-1062-1]