Syndecan 1 Explained

Syndecan 1 is a protein which in humans is encoded by the SDC1 gene.[1] [2] 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,[3] 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.[4] The extracellular domain can be cleaved (shed) from the cell surface at a juxtamembrane site,[5] converting the membrane-bound proteoglycan into a paracrine effector molecule with roles in wound repair [6] and invasive growth of cancer cells.[7]

An exception is the prosecretory mitogen lacritin that binds syndecan-1 only after heparanase modification.[8] [9] 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. 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. 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.

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.[10]

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)[11] to the inflamed endothelium.[12] This increase results in higher inflammatory responses and tissue damage in experimental models of contact dermatitis,[13] inflammation of the kidney,[14] myocardial infarction,[15] inflammatory bowel disease[16] and experimental autoimmune encephalomyelitis[17] In experimental colitis-induced colon carcinoma, syndecan-1 deficiency promotes tumor growth in an IL-6 / STAT-signaling-dependent manner.[18]

Clinical significance

Altered syndecan-1 expression has been detected in several different tumor types.[19] [20] 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 [21] [22] [23]

It is a specific antigen on multiple myeloma cells.[24] Indatuximab ravtansine targets this protein.

Application

It is a useful marker for plasma cells,[25] but only if the cells tested are already known to be derived from blood.[26] For plasma cells, it usually stains intensely membranous, with or without associated diffuse weak cytoplasmic and/or Golgi staining.[27] Few cases show cytoplasmic granular staining, with or without associated Golgi staining.[27]

Further reading

Notes and References

  1. Mali M, Jaakkola P, Arvilommi AM, Jalkanen M . Sequence of human syndecan indicates a novel gene family of integral membrane proteoglycans . The Journal of Biological Chemistry . 265 . 12 . 6884–6889 . April 1990 . 2324102 . 10.1016/S0021-9258(19)39232-4 . free .
  2. Ala-Kapee M, Nevanlinna H, Mali M, Jalkanen M, Schröder J . 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 . September 1990 . 2173154 . 10.1007/BF01233200 . 43270934 .
  3. Götte M . Syndecans in inflammation . FASEB Journal . 17 . 6 . 575–591 . April 2003 . 12665470 . 10.1096/fj.02-0739rev . free . 16948257 .
  4. Bernfield M, Götte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, Zako M . Functions of cell surface heparan sulfate proteoglycans . Annual Review of Biochemistry . 68 . 729–777 . 1999 . 10872465 . 10.1146/annurev.biochem.68.1.729 .
  5. Wang Z, Götte M, Bernfield M, Reizes O . 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 . September 2005 . 16156648 . 2546870 . 10.1021/bi050620i .
  6. Elenius V, Götte M, Reizes O, Elenius K, Bernfield M . Inhibition by the soluble syndecan-1 ectodomains delays wound repair in mice overexpressing syndecan-1 . The Journal of Biological Chemistry . 279 . 40 . 41928–41935 . October 2004 . 15220342 . 10.1074/jbc.M404506200 . free .
  7. Piperigkou Z, Mohr B, Karamanos N, Götte M . Shed proteoglycans in tumor stroma . Cell and Tissue Research . 365 . 3 . 643–655 . September 2016 . 27365088 . 10.1007/s00441-016-2452-4 . 13944019 .
  8. Ma P, Beck SL, Raab RW, McKown RL, Coffman GL, Utani A, Chirico WJ, Rapraeger AC, Laurie GW . 6 . 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 . September 2006 . 16982797 . 1666580 . 10.1083/jcb.200511134 .
  9. Zhang Y, Wang N, Raab RW, McKown RL, Irwin JA, Kwon I, van Kuppevelt TH, Laurie GW . 6 . 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 . April 2013 . 23504321 . 3636894 . 10.1074/jbc.M112.422717 . free .
  10. Web site: Entrez Gene: SDC1 syndecan 1.
  11. Averbeck M, Kuhn S, Bühligen J, Götte M, Simon JC, Polte T . Syndecan-1 regulates dendritic cell migration in cutaneous hypersensitivity to haptens . Experimental Dermatology . 26 . 11 . 1060–1067 . November 2017 . 28453867 . 10.1111/exd.13374 . 38757296 .
  12. Götte M, Joussen AM, Klein C, Andre P, Wagner DD, Hinkes MT, Kirchhof B, Adamis AP, Bernfield M . 6 . Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature . Investigative Ophthalmology & Visual Science . 43 . 4 . 1135–1141 . April 2002 . 11923257 .
  13. Kharabi Masouleh B, Ten Dam GB, Wild MK, Seelige R, van der Vlag J, Rops AL, Echtermeyer FG, Vestweber D, van Kuppevelt TH, Kiesel L, Götte M . 6 . Role of the heparan sulfate proteoglycan syndecan-1 (CD138) in delayed-type hypersensitivity . Journal of Immunology . 182 . 8 . 4985–4993 . April 2009 . 19342678 . 10.4049/jimmunol.0800574 . free .
  14. Rops AL, Götte M, Baselmans MH, van den Hoven MJ, Steenbergen EJ, Lensen JF, Wijnhoven TJ, Cevikbas F, van den Heuvel LP, van Kuppevelt TH, Berden JH, van der Vlag J . 6 . Syndecan-1 deficiency aggravates anti-glomerular basement membrane nephritis . Kidney International . 72 . 10 . 1204–1215 . November 2007 . 17805240 . 10.1038/sj.ki.5002514 . free .
  15. Vanhoutte D, Schellings MW, Götte M, Swinnen M, Herias V, Wild MK, Vestweber D, Chorianopoulos E, Cortés V, Rigotti A, Stepp MA, Van de Werf F, Carmeliet P, Pinto YM, Heymans S . 6 . Increased expression of syndecan-1 protects against cardiac dilatation and dysfunction after myocardial infarction . Circulation . 115 . 4 . 475–482 . January 2007 . 17242279 . 10.1161/CIRCULATIONAHA.106.644609 . free .
  16. Floer M, Götte M, Wild MK, Heidemann J, Gassar ES, Domschke W, Kiesel L, Luegering A, Kucharzik T . 6 . Enoxaparin improves the course of dextran sodium sulfate-induced colitis in syndecan-1-deficient mice . The American Journal of Pathology . 176 . 1 . 146–157 . January 2010 . 20008145 . 2797877 . 10.2353/ajpath.2010.080639 .
  17. Zhang X, Wu C, Song J, Götte M, Sorokin L . 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 . November 2013 . 24078687 . 10.4049/jimmunol.1300931 . free .
  18. Binder Gallimidi A, Nussbaum G, Hermano E, Weizman B, Meirovitz A, Vlodavsky I, Götte M, Elkin M . 6 . Syndecan-1 deficiency promotes tumor growth in a murine model of colitis-induced colon carcinoma . PLOS ONE . 12 . 3 . e0174343 . 2017 . 28350804 . 5369774 . 10.1371/journal.pone.0174343 . free . 2017PLoSO..1274343B .
  19. Yip GW, Smollich M, Götte M . Therapeutic value of glycosaminoglycans in cancer . Molecular Cancer Therapeutics . 5 . 9 . 2139–2148 . September 2006 . 16985046 . 10.1158/1535-7163.MCT-06-0082 . free .
  20. Stepp MA, Pal-Ghosh S, Tadvalkar G, Pajoohesh-Ganji A . Syndecan-1 and Its Expanding List of Contacts . Advances in Wound Care . 4 . 4 . 235–249 . April 2015 . 25945286 . 4397989 . 10.1089/wound.2014.0555 .
  21. Hassan H, Greve B, Pavao MS, Kiesel L, Ibrahim SA, Götte M . 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 . May 2013 . 23289672 . 10.1111/febs.12111 . 19929711 .
  22. Ibrahim SA, Gadalla R, El-Ghonaimy EA, Samir O, Mohamed HT, Hassan H, Greve B, El-Shinawi M, Mohamed MM, Götte M . 6 . 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 . March 2017 . 28270211 . 5341174 . 10.1186/s12943-017-0621-z . free .
  23. Götte M, Kersting C, Ruggiero M, Tio J, Tulusan AH, Kiesel L, Wülfing P . Predictive value of syndecan-1 expression for the response to neoadjuvant chemotherapy of primary breast cancer . Anticancer Research . 26 . 1B . 621–627 . 2006 . 16739330 .
  24. http://www.myelomabeacon.com/resources/mtgs/ash2013/abs/758/ 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
  25. Book: Rawstron AC . Chapter 6: Immunophenotyping of plasma cells . Current Protocols in Cytometry . 1 . Unit 6.23 . May 2006 . Chapter 6 . 18770841 . 10.1002/0471142956.cy0623s36 . 0471142956 . 19511070 .
  26. O'Connell FP, Pinkus JL, Pinkus GS . CD138 (syndecan-1), a plasma cell marker immunohistochemical profile in hematopoietic and nonhematopoietic neoplasms . American Journal of Clinical Pathology . 121 . 2 . 254–263 . February 2004 . 14983940 . 10.1309/617D-WB5G-NFWX-HW4L . free . Geraldine Pinkus .
  27. Al-Quran SZ, Yang L, Magill JM, Braylan RC, Douglas-Nikitin VK . Assessment of bone marrow plasma cell infiltrates in multiple myeloma: the added value of CD138 immunohistochemistry . Human Pathology . 38 . 12 . 1779–1787 . December 2007 . 17714757 . 3419754 . 10.1016/j.humpath.2007.04.010 .

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