Syndecan 1

Last updated
SDC1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SDC1 , CD138, SDC, SYND1, syndecan, syndecan 1
External IDs OMIM: 186355 MGI: 1349162 HomoloGene: 2252 GeneCards: SDC1
Orthologs
SpeciesHumanMouse
Entrez

6382

20969

Ensembl

ENSG00000115884

ENSMUSG00000020592

UniProt

P18827

P18828

RefSeq (mRNA)

NM_001006946
NM_002997

NM_011519

RefSeq (protein)

NP_001006947
NP_002988

NP_035649

Location (UCSC) Chr 2: 20.2 – 20.23 Mb Chr 12: 8.82 – 8.84 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Syndecan 1 is a protein which in humans is encoded by the SDC1 gene. [5] [6] The protein is a transmembrane (type I) heparan sulfate proteoglycan and is a member of the syndecan proteoglycan family. The syndecan-1 protein functions as an integral membrane protein and participates in cell proliferation, cell migration and cell-matrix interactions via its receptor for extracellular matrix proteins. Syndecan-1 is a sponge for growth factors and chemokines, [7] with binding largely via heparan sulfate chains. The syndecans mediate cell binding, cell signaling, and cytoskeletal organization and syndecan receptors are required for internalization of the HIV-1 tat protein.

Contents

Altered syndecan-1 expression has been detected in several different tumor types. Syndecan 1 can be a marker for plasma cells.

Structure

The syndecan-1 core protein consists of an extracellular domain which can be substituted with heparan sulfate and chondroitin sulfate glycosaminoglycan chains, a highly conserved transmembrane domain, and a highly conserved cytoplasmic domain, which contains two constant regions that are separated by a variable region. [8] The extracellular domain can be cleaved (shed) from the cell surface at a juxtamembrane site, [9] converting the membrane-bound proteoglycan into a paracrine effector molecule with roles in wound repair [10] and invasive growth of cancer cells. [11]

An exception is the prosecretory mitogen lacritin that binds syndecan-1 only after heparanase modification. [12] [13] Binding utilizes an enzyme-regulated 'off-on' switch in which active epithelial heparanase (HPSE) cleaves off heparan sulfate to expose a binding site in the N-terminal region of syndecan-1's core protein. [12] Three SDC1 elements are required. (1) The heparanase-exposed hydrophobic sequence GAGAL that promotes the alpha helicity of lacritin's C-terminal amphipathic alpha helix form and likely binds to the hydrophobic face. (2) Heparanase-cleaved heparan sulfate that is 3-O sulfated. [13] This likely interacts with the cationic face of lacritin's C-terminal amphipathic alpha helix. (3) An N-terminal chondroitin sulfate chain that also likely binds to the cationic face. Point mutagenesis of lacritin has narrowed the ligation site. [13]

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. [14]

Inflammation

Syndecan-1 deficient mice show increased inflammation, which was attributed to an increased ICAM-1 and heparan sulfate-dependent recruitment of leukocytes (including neutrophils and dendritic cells) [15] to the inflamed endothelium. [16] This increase results in higher inflammatory responses and tissue damage in experimental models of contact dermatitis, [17] inflammation of the kidney, [18] myocardial infarction, [19] inflammatory bowel disease [20] and experimental autoimmune encephalomyelitis [21] In experimental colitis-induced colon carcinoma, syndecan-1 deficiency promotes tumor growth in an IL-6 / STAT-signaling-dependent manner. [22]

Clinical significance

Altered syndecan-1 expression has been detected in several different tumor types. [23] [24] In breast cancer, syndecan-1 is up regulated and contributes to the cancer stem cell phenotype, which is linked to increased resistance to chemotherapy and radiation therapy [25] [26] [27]

It is a specific antigen on multiple myeloma cells. [28] Indatuximab ravtansine targets this protein.

Application

It is a useful marker for plasma cells, [29] but only if the cells tested are already known to be derived from blood. [30] For plasma cells, it usually stains intensely membranous, with or without associated diffuse weak cytoplasmic and/or Golgi staining. [31] Few cases show cytoplasmic granular staining, with or without associated Golgi staining. [31]

Related Research Articles

<span class="mw-page-title-main">Proteoglycan</span> Class of compounds

Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge. The Ser residue is generally in the sequence -Ser-Gly-X-Gly-, although not every protein with this sequence has an attached glycosaminoglycan. The chains are long, linear carbohydrate polymers that are negatively charged under physiological conditions due to the occurrence of sulfate and uronic acid groups. Proteoglycans occur in connective tissue.

<span class="mw-page-title-main">Glycosaminoglycan</span> Polysaccharides found in animal tissue

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

<span class="mw-page-title-main">Perlecan</span>

Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the HSPG2 gene. The HSPG2 gene codes for a 4,391 amino acid protein with a molecular weight of 468,829. It is one of the largest known proteins. The name perlecan comes from its appearance as a "string of pearls" in rotary shadowed images.

<span class="mw-page-title-main">Heparan sulfate</span> Macromolecule

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

<span class="mw-page-title-main">Lacritin</span>

Lacritin is a 12.3 kDa glycoprotein encoded in humans by the LACRT gene. Lacritin's discovery emerged from a screen for factors that stimulate tear protein secretion. Lacritin is a secreted protein found in tears and saliva. Lacritin also promotes tear secretion, the proliferation and survival of epithelial cells, and corneal wound healing Lacritin is thus a multifunctional prosecretory mitogen with cell survival activity. Natural or bacterial cleavage of lacritin releases a C-terminal fragment that is bactericidal.

<span class="mw-page-title-main">Syndecan</span>

Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. More specifically, these core proteins carry three to five heparan sulfate and chondroitin sulfate chains, i.e. they are proteoglycans, which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin C.

<span class="mw-page-title-main">Syndecan-2</span> Protein-coding gene in the species Homo sapiens

Syndecan-2 is a protein that in humans is encoded by the SDC2 gene.

<span class="mw-page-title-main">Syndecan-4</span> Protein-coding gene in the species Homo sapiens

Syndecan-4 is a protein that in humans is encoded by the SDC4 gene. Syndecan-4 is one of the four vertebrate syndecans and has a molecular weight of ~20 kDa. Syndecans are the best-characterized plasma membrane proteoglycans. Their intracellular domain of membrane-spanning core protein interacts with actin cytoskeleton and signaling molecules in the cell cortex. Syndecans are normally found on the cell surface of fibroblasts and epithelial cells. Syndecans interact with fibronectin on the cell surface, cytoskeletal and signaling proteins inside the cell to modulate the function of integrin in cell-matrix adhesion. Also, syndecans bind to FGFs and bring them to the FGF receptor on the same cell. As a co-receptor or regulator, mutated certain proteoglycans could cause severe developmental defects, like disordered distribution or inactivation of signaling molecules.

<span class="mw-page-title-main">CASK</span> Protein-coding gene in humans

Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2, calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2. CASK gene mutations are the cause of XL-ID with or without nystagmus and MICPCH, an X-linked neurological disorder.

<span class="mw-page-title-main">Heparanase</span> Mammalian protein found in Homo sapiens

Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.

<span class="mw-page-title-main">Glypican 3</span> Protein-coding gene in the species Homo sapiens

Glypican-3 is a protein that, in humans, is encoded by the GPC3 gene. The GPC3 gene is located on human X chromosome (Xq26) where the most common gene encodes a 70-kDa core protein with 580 amino acids. Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).

<span class="mw-page-title-main">Syndecan-3</span> Protein-coding gene in the species Homo sapiens

Syndecan-3 is a protein that in humans is encoded by the SDC3 gene.

<span class="mw-page-title-main">CSPG4</span> Protein-coding gene in the species Homo sapiens

Chondroitin sulfate proteoglycan 4, also known as melanoma-associated chondroitin sulfate proteoglycan (MCSP) or neuron-glial antigen 2 (NG2), is a chondroitin sulfate proteoglycan that in humans is encoded by the CSPG4 gene.

<span class="mw-page-title-main">Glypican 1</span> Protein-coding gene in the species Homo sapiens

Glypican-1 (GPC1) is a protein that in humans is encoded by the GPC1 gene. GPC1 is encoded by human GPC1 gene located at 2q37.3. GPC1 contains 558 amino acids with three predicted heparan sulfate chains.

<span class="mw-page-title-main">SPOCK1</span> Protein-coding gene in the species Homo sapiens

Testican-1 is a protein that in humans is encoded by the SPOCK1 gene.

<span class="mw-page-title-main">B4GALT7</span> Protein-coding gene in the species Homo sapiens

Beta-1,4-galactosyltransferase 7 also known as galactosyltransferase I is an enzyme that in humans is encoded by the B4GALT7 gene. Galactosyltransferase I catalyzes the synthesis of the glycosaminoglycan-protein linkage in proteoglycans. Proteoglycans in turn are structural components of the extracellular matrix that is found between cells in connective tissues.

<span class="mw-page-title-main">SULF1</span> Protein-coding gene in the species Homo sapiens

Sulfatase 1, also known as SULF1, is an enzyme which in humans is encoded by the SULF1 gene.

<span class="mw-page-title-main">SULF2</span> Protein-coding gene in the species Homo sapiens

Extracellular sulfatase Sulf-2 is an enzyme that in humans is encoded by the SULF2 gene.

<span class="mw-page-title-main">XYLT2</span> Protein-coding gene in the species Homo sapiens

Xylosyltransferase 2 is an enzyme that in humans is encoded by the XYLT2 gene.

Heparanase is an enzyme with systematic name heparan sulfate N-sulfo-D-glucosamine endoglucanase. This enzyme catalyses the following chemical reaction

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115884 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020592 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Mali M, Jaakkola P, Arvilommi AM, Jalkanen M (April 1990). "Sequence of human syndecan indicates a novel gene family of integral membrane proteoglycans". The Journal of Biological Chemistry. 265 (12): 6884–6889. doi: 10.1016/S0021-9258(19)39232-4 . PMID   2324102.
  6. ↑ Ala-Kapee M, Nevanlinna H, Mali M, Jalkanen M, Schröder J (September 1990). "Localization of gene for human syndecan, an integral membrane proteoglycan and a matrix receptor, to chromosome 2". Somatic Cell and Molecular Genetics. 16 (5): 501–505. doi:10.1007/BF01233200. PMID   2173154. S2CID   43270934.
  7. ↑ Götte M (April 2003). "Syndecans in inflammation". FASEB Journal. 17 (6): 575–591. doi:10.1096/fj.02-0739rev. PMID   12665470. S2CID   16948257.
  8. ↑ Bernfield M, Götte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, Zako M (1999). "Functions of cell surface heparan sulfate proteoglycans". Annual Review of Biochemistry. 68: 729–777. doi:10.1146/annurev.biochem.68.1.729. PMID   10872465.
  9. ↑ Wang Z, Götte M, Bernfield M, Reizes O (September 2005). "Constitutive and accelerated shedding of murine syndecan-1 is mediated by cleavage of its core protein at a specific juxtamembrane site". Biochemistry. 44 (37): 12355–12361. doi:10.1021/bi050620i. PMC   2546870 . PMID   16156648.
  10. ↑ Elenius V, Götte M, Reizes O, Elenius K, Bernfield M (October 2004). "Inhibition by the soluble syndecan-1 ectodomains delays wound repair in mice overexpressing syndecan-1". The Journal of Biological Chemistry. 279 (40): 41928–41935. doi: 10.1074/jbc.M404506200 . PMID   15220342.
  11. ↑ Piperigkou Z, Mohr B, Karamanos N, Götte M (September 2016). "Shed proteoglycans in tumor stroma". Cell and Tissue Research. 365 (3): 643–655. doi:10.1007/s00441-016-2452-4. PMID   27365088. S2CID   13944019.
  12. 1 2 Ma P, Beck SL, Raab RW, McKown RL, Coffman GL, Utani A, et al. (September 2006). "Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin". The Journal of Cell Biology. 174 (7): 1097–1106. doi:10.1083/jcb.200511134. PMC   1666580 . PMID   16982797.
  13. 1 2 3 Zhang Y, Wang N, Raab RW, McKown RL, Irwin JA, Kwon I, et al. (April 2013). "Targeting of heparanase-modified syndecan-1 by prosecretory mitogen lacritin requires conserved core GAGAL plus heparan and chondroitin sulfate as a novel hybrid binding site that enhances selectivity". The Journal of Biological Chemistry. 288 (17): 12090–12101. doi: 10.1074/jbc.M112.422717 . PMC   3636894 . PMID   23504321.
  14. ↑ "Entrez Gene: SDC1 syndecan 1".
  15. ↑ Averbeck M, Kuhn S, Bühligen J, Götte M, Simon JC, Polte T (November 2017). "Syndecan-1 regulates dendritic cell migration in cutaneous hypersensitivity to haptens". Experimental Dermatology. 26 (11): 1060–1067. doi:10.1111/exd.13374. PMID   28453867. S2CID   38757296.
  16. ↑ Götte M, Joussen AM, Klein C, Andre P, Wagner DD, Hinkes MT, et al. (April 2002). "Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature". Investigative Ophthalmology & Visual Science. 43 (4): 1135–1141. PMID   11923257.
  17. ↑ Kharabi Masouleh B, Ten Dam GB, Wild MK, Seelige R, van der Vlag J, Rops AL, et al. (April 2009). "Role of the heparan sulfate proteoglycan syndecan-1 (CD138) in delayed-type hypersensitivity". Journal of Immunology. 182 (8): 4985–4993. doi: 10.4049/jimmunol.0800574 . PMID   19342678.
  18. ↑ Rops AL, Götte M, Baselmans MH, van den Hoven MJ, Steenbergen EJ, Lensen JF, et al. (November 2007). "Syndecan-1 deficiency aggravates anti-glomerular basement membrane nephritis". Kidney International. 72 (10): 1204–1215. doi: 10.1038/sj.ki.5002514 . PMID   17805240.
  19. ↑ Vanhoutte D, Schellings MW, Götte M, Swinnen M, Herias V, Wild MK, et al. (January 2007). "Increased expression of syndecan-1 protects against cardiac dilatation and dysfunction after myocardial infarction" (PDF). Circulation. 115 (4): 475–482. doi: 10.1161/CIRCULATIONAHA.106.644609 . PMID   17242279.
  20. ↑ Floer M, Götte M, Wild MK, Heidemann J, Gassar ES, Domschke W, et al. (January 2010). "Enoxaparin improves the course of dextran sodium sulfate-induced colitis in syndecan-1-deficient mice". The American Journal of Pathology. 176 (1): 146–157. doi:10.2353/ajpath.2010.080639. PMC   2797877 . PMID   20008145.
  21. ↑ Zhang X, Wu C, Song J, Götte M, Sorokin L (November 2013). "Syndecan-1, a cell surface proteoglycan, negatively regulates initial leukocyte recruitment to the brain across the choroid plexus in murine experimental autoimmune encephalomyelitis". Journal of Immunology. 191 (9): 4551–4561. doi: 10.4049/jimmunol.1300931 . PMID   24078687.
  22. ↑ Binder Gallimidi A, Nussbaum G, Hermano E, Weizman B, Meirovitz A, Vlodavsky I, et al. (2017). "Syndecan-1 deficiency promotes tumor growth in a murine model of colitis-induced colon carcinoma". PLOS ONE. 12 (3): e0174343. Bibcode:2017PLoSO..1274343B. doi: 10.1371/journal.pone.0174343 . PMC   5369774 . PMID   28350804.
  23. ↑ Yip GW, Smollich M, Götte M (September 2006). "Therapeutic value of glycosaminoglycans in cancer" (PDF). Molecular Cancer Therapeutics. 5 (9): 2139–2148. doi: 10.1158/1535-7163.MCT-06-0082 . PMID   16985046.
  24. ↑ Stepp MA, Pal-Ghosh S, Tadvalkar G, Pajoohesh-Ganji A (April 2015). "Syndecan-1 and Its Expanding List of Contacts". Advances in Wound Care. 4 (4): 235–249. doi:10.1089/wound.2014.0555. PMC   4397989 . PMID   25945286.
  25. ↑ Hassan H, Greve B, Pavao MS, Kiesel L, Ibrahim SA, Götte M (May 2013). "Syndecan-1 modulates β-integrin-dependent and interleukin-6-dependent functions in breast cancer cell adhesion, migration, and resistance to irradiation". The FEBS Journal. 280 (10): 2216–2227. doi:10.1111/febs.12111. PMID   23289672. S2CID   19929711.
  26. ↑ Ibrahim SA, Gadalla R, El-Ghonaimy EA, Samir O, Mohamed HT, Hassan H, et al. (March 2017). "Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways". Molecular Cancer. 16 (1): 57. doi: 10.1186/s12943-017-0621-z . PMC   5341174 . PMID   28270211.
  27. ↑ Götte M, Kersting C, Ruggiero M, Tio J, Tulusan AH, Kiesel L, Wülfing P (2006). "Predictive value of syndecan-1 expression for the response to neoadjuvant chemotherapy of primary breast cancer". Anticancer Research. 26 (1B): 621–627. PMID   16739330.
  28. ↑ Indatuximab Ravtansine (BT062) In Combination With Lenalidomide and Low-Dose Dexamethasone In Patients With Relapsed and/Or Refractory Multiple Myeloma: Clinical Activity In Len/Dex-Refractory Patients
  29. ↑ Rawstron AC (May 2006). "Chapter 6: Immunophenotyping of plasma cells". Current Protocols in Cytometry. Vol. Chapter 6. pp. Unit 6.23. doi:10.1002/0471142956.cy0623s36. ISBN   0471142956. PMID   18770841. S2CID   19511070.
  30. ↑ O'Connell FP, Pinkus JL, Pinkus GS (February 2004). "CD138 (syndecan-1), a plasma cell marker immunohistochemical profile in hematopoietic and nonhematopoietic neoplasms". American Journal of Clinical Pathology. 121 (2): 254–263. doi: 10.1309/617D-WB5G-NFWX-HW4L . PMID   14983940.[ permanent dead link ]
  31. 1 2 Al-Quran SZ, Yang L, Magill JM, Braylan RC, Douglas-Nikitin VK (December 2007). "Assessment of bone marrow plasma cell infiltrates in multiple myeloma: the added value of CD138 immunohistochemistry". Human Pathology. 38 (12): 1779–1787. doi:10.1016/j.humpath.2007.04.010. PMC   3419754 . PMID   17714757.

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