SDC1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSDC1, CD138, SDC, SYND1, syndecan, syndecan 1
External IDsOMIM: 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 MbChr 12: 8.82 – 8.84 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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.

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]

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.
  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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