Syndecan-4 Explained

Syndecan-4 is a protein that in humans is encoded by the SDC4 gene.^{[1] [2]} 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.

Syndecans have similar structural features:

• Attach to heparan sulfate chains – interacting factors (e.g. Matrix molecules, growth factors, and enzymes)
• Chondroitin sulfate chain
• Transmembrane domain – self-association
• C1 domain – actin-association cytoskeleton
• Variable domain – syndecan-specific
• C2 domain – attach to PDZ proteins

Syndecans normally form homodimers or multimers. Their biological function includes cell growth regulation, differentiation, and adhesion.Syndecan-4 has more widespread distribution than other syndecans and it is the only syndecan that has been found consistently in focal adhesions.^[3]

Gene

Syndecan-4 is also called ryudocan or amphiglycan. It is found on chromosome 20, while a pseudogene has been found on chromosome 22.^[4] Syndecan-4 is one of the four vertebrate syndecans and has a molecular weight of ~20 kDa. It has more widespread distribution than other syndecans, and it is the only syndecan that has been found consistently in focal adhesions.^[5]

Function

Syndecan-4 is a transmembrane (type I) heparan sulfate proteoglycan that functions as a receptor in intracellular signaling. The protein is found as a homodimer and is a member of the syndecan proteoglycan family.^[4] Syndecan-4 interacts with extracellular matrix, anticoagulants, and growth-factors. It also regulates the actin cytoskeleton, cell adhesion, and cell migration.^[6]

Syndecan-4 activates protein kinase C (PKC), an enzyme involved in signal transduction.^[7] The variable domain of syndecan-4 could be a site of self-association. The degree of oligomerization correlates with the activity of kinases, so the degree of clustering of syndecan-4 correlates to PKC activity.^[8] Syndecan-4 also binds to phosphatidylinositol (4,5)-bisphosphate (PIP2) through the variable domain and increases PKC activity ten-fold.^[9]

Syndecan-4 is also a regulator of fibroblast growth factor-2 (FGF-2) signaling. Syndecan-4 binds to FGF and mediates interaction with the FGF receptor.^[10] Because the tight correlation between syndecan-4 and growth factors, the efficiency of angiogenic therapies have been thought to relate to syndecan-4. Growth factor signaling may be disrupted by changes in syndecan-4 expression.^{[11] [12] [13]} The cellular uptake, trafficking, and nuclear localization of FGF-2 could be increased by co-delivery of syndecan-4 proteoliposomes. These alterations should be considered in FGF-2-based therapies.^[14]

Syndecan-4 is also associated with the healing process. Lack of Sdc4 gene causes delayed wound healing in mice. This delay may be due to compromised fibroblast motility.^[15]

Clinical significance

Endometriosis

Syndecan-4 expression is upregulated in the endometrium of women suffering from endometriosis, and its downregulation in endometriotic cells results in a decrease of invasive growth, and reduced expression of the small GTPase Rac1, Activating transcription factor 2 (ATF2), and MMP3. ^[16]

Osteoarthritis

Syndecan-4 is upregulated in osteoarthritis and inhibition of syndecan-4 reduces cartilage destruction in mouse models of OA.^[17]

See Sindecán-4 at the Spanish Wikipedia

Further reading

• Bass MD, Humphries MJ . Cytoplasmic interactions of syndecan-4 orchestrate adhesion receptor and growth factor receptor signalling . Biochem. J. . 368 . Pt 1 . 1–15 . 2002 . 12241528 . 10.1042/BJ20021228 . 1222989 .
• Yu H, Humphries DE, Watkins M, Karlinsky JB . Molecular cloning of the human ryudocan promoter . Biochem. Biophys. Res. Commun. . 212 . 3 . 1139–44 . 1995 . 7626103 . 10.1006/bbrc.1995.2087 . free .
• Barillari G, Gendelman R, Gallo RC, Ensoli B . The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence . Proc. Natl. Acad. Sci. U.S.A. . 90 . 17 . 7941–5 . 1993 . 7690138 . 10.1073/pnas.90.17.7941 . 47263 . 1993PNAS...90.7941B . free .
• Woods A, Couchman JR . Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component . Mol. Biol. Cell . 5 . 2 . 183–92 . 1994 . 8019004 . 10.1091/mbc.5.2.183. 301024 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Albini A, Benelli R, Presta M, Rusnati M, Ziche M, Rubartelli A, Paglialunga G, Bussolino F, Noonan D . HIV-tat protein is a heparin-binding angiogenic growth factor . Oncogene . 12 . 2 . 289–97 . 1996 . 8570206 .
• Kojima T, Katsumi A, Yamazaki T, Muramatsu T, Nagasaka T, Ohsumi K, Saito H . Human ryudocan from endothelium-like cells binds basic fibroblast growth factor, midkine, and tissue factor pathway inhibitor . J. Biol. Chem. . 271 . 10 . 5914–20 . 1996 . 8621465 . 10.1074/jbc.271.10.5914 . free .
• Takagi A, Kojima T, Tsuzuki S, Katsumi A, Yamazaki T, Sugiura I, Hamaguchi M, Saito H . Structural organization and promoter activity of the human ryudocan gene . J. Biochem. . 119 . 5 . 979–84 . 1997 . 8797100 . 10.1093/oxfordjournals.jbchem.a021338 .
• Rusnati M, Coltrini D, Oreste P, Zoppetti G, Albini A, Noonan D, d'Adda di Fagagna F, Giacca M, Presta M . Interaction of HIV-1 Tat protein with heparin. Role of the backbone structure, sulfation, and size . J. Biol. Chem. . 272 . 17 . 11313–20 . 1997 . 9111037 . 10.1074/jbc.272.17.11313 . free .
• Chang HC, Samaniego F, Nair BC, Buonaguro L, Ensoli B . HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region . AIDS . 11 . 12 . 1421–31 . 1997 . 9342064 . 10.1097/00002030-199712000-00006 . 7648619 . free .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Horowitz A, Simons M . Regulation of syndecan-4 phosphorylation in vivo . J. Biol. Chem. . 273 . 18 . 10914–8 . 1998 . 9556568 . 10.1074/jbc.273.18.10914 . free .
• Lee D, Oh ES, Woods A, Couchman JR, Lee W . Solution structure of a syndecan-4 cytoplasmic domain and its interaction with phosphatidylinositol 4,5-bisphosphate . J. Biol. Chem. . 273 . 21 . 13022–9 . 1998 . 9582338 . 10.1074/jbc.273.21.13022 . free .
• Cohen AR, Woods DF, Marfatia SM, Walther Z, Chishti AH, Anderson JM . Human CASK/LIN-2 Binds Syndecan-2 and Protein 4.1 and Localizes to the Basolateral Membrane of Epithelial Cells . J. Cell Biol. . 142 . 1 . 129–38 . 1998 . 9660868 . 10.1083/jcb.142.1.129 . 2133028 .
• Rusnati M, Tulipano G, Spillmann D, Tanghetti E, Oreste P, Zoppetti G, Giacca M, Presta M . Multiple interactions of HIV-I Tat protein with size-defined heparin oligosaccharides . J. Biol. Chem. . 274 . 40 . 28198–205 . 1999 . 10497173 . 10.1074/jbc.274.40.28198 . free .
• Gao Y, Li M, Chen W, Simons M . Synectin, syndecan-4 cytoplasmic domain binding PDZ protein, inhibits cell migration . J. Cell. Physiol. . 184 . 3 . 373–9 . 2000 . 10911369 . 10.1002/1097-4652(200009)184:3<373::AID-JCP12>3.0.CO;2-I . 20829740 .
• Tyagi M, Rusnati M, Presta M, Giacca M . Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans . J. Biol. Chem. . 276 . 5 . 3254–61 . 2001 . 11024024 . 10.1074/jbc.M006701200 . free .
• Shin J, Lee W, Lee D, Koo BK, Han I, Lim Y, Woods A, Couchman JR, Oh ES . Solution structure of the dimeric cytoplasmic domain of syndecan-4 . Biochemistry . 40 . 29 . 8471–8 . 2001 . 11456484 . 10.1021/bi002750r .

Notes and References

1. Kojima T, Inazawa J, Takamatsu J, Rosenberg RD, Saito H . Human ryudocan core protein: molecular cloning and characterization of the cDNA, and chromosomal localization of the gene . Biochem Biophys Res Commun . 190 . 3 . 814–22 . Mar 1993 . 7916598 . 10.1006/bbrc.1993.1122 .
2. David G, van der Schueren B, Marynen P, Cassiman JJ, van den Berghe H . Molecular cloning of amphiglycan, a novel integral membrane heparan sulfate proteoglycan expressed by epithelial and fibroblastic cells . J Cell Biol . 118 . 4 . 961–9 . Sep 1992 . 1500433 . 2289559 . 10.1083/jcb.118.4.961 .
3. Woods A, Couchman JR . 1994 . Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component . Mol Biol Cell . 5 . 2. 183–192 . 8019004 . 301024 . 10.1091/mbc.5.2.183.
4. Web site: Entrez Gene: SDC4 syndecan 4.
5. Woods A, Couchman JR . Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component . Mol. Biol. Cell . 5 . 2 . 183–92 . February 1994 . 8019004 . 301024 . 10.1091/mbc.5.2.183.
6. Woods A, Couchman JR . Syndecans: synergistic activators of cell adhesion . Trends Cell Biol. . 8 . 5 . 189–92 . May 1998 . 9695837 . 10.1016/S0962-8924(98)01244-6 .
7. Hyatt SL, Klauck T, Jaken S . Protein kinase C is localized in focal contacts of normal but not transformed fibroblasts . Mol. Carcinog. . 3 . 2 . 45–53 . 1990 . 2161238 . 10.1002/mc.2940030202 . 46254921 .
8. Grootjans JJ, Zimmermann P, Reekmans G, Smets A, Degeest G, Dürr J, David G . Syntenin, a PDZ protein that binds syndecan cytoplasmic domains . Proc. Natl. Acad. Sci. U.S.A. . 94 . 25 . 13683–8 . December 1997 . 9391086 . 28366 . 10.1073/pnas.94.25.13683 . 1997PNAS...9413683G . free .
9. Oh ES, Woods A, Couchman JR . Multimerization of the cytoplasmic domain of syndecan-4 is required for its ability to activate protein kinase C . J. Biol. Chem. . 272 . 18 . 11805–11 . May 1997 . 9115237 . 10.1074/jbc.272.18.11805 . free .
10. Chua CC, Rahimi N, Forsten-Williams K, Nugent MA . Heparan sulfate proteoglycans function as receptors for fibroblast growth factor-2 activation of extracellular signal-regulated kinases 1 and 2 . Circ. Res. . 94 . 3 . 316–23 . February 2004 . 14684627 . 10.1161/01.RES.0000112965.70691.AC . free .
11. Bortoff KD, Wagner WD . Reduced syndecan-4 expression in arterial smooth muscle cells with enhanced proliferation . Exp. Mol. Pathol. . 78 . 1 . 10–6 . February 2005 . 15596055 . 10.1016/j.yexmp.2004.08.010 .
12. Neelapu SS, Gause BL, Harvey L, Lee ST, Frye AR, Horton J, Robb RJ, Popescu MC, Kwak LW . A novel proteoliposomal vaccine induces antitumor immunity against follicular lymphoma . Blood . 109 . 12 . 5160–3 . June 2007 . 17339422 . 1941785 . 10.1182/blood-2006-12-063594 .
13. Olsson U, Bondjers G, Camejo G . Fatty acids modulate the composition of extracellular matrix in cultured human arterial smooth muscle cells by altering the expression of genes for proteoglycan core proteins . Diabetes . 48 . 3 . 616–22 . March 1999 . 10078565 . 10.2337/diabetes.48.3.616 .
14. Jang E, Albadawi H, Watkins MT, Edelman ER, Baker AB . Syndecan-4 proteoliposomes enhance fibroblast growth factor-2 (FGF-2)-induced proliferation, migration, and neovascularization of ischemic muscle . Proc. Natl. Acad. Sci. U.S.A. . 109 . 5 . 1679–84 . January 2012 . 22307630 . 3277125 . 10.1073/pnas.1117885109 . 2012PNAS..109.1679J . free .
15. Echtermeyer F, Streit M, Wilcox-Adelman S, Saoncella S, Denhez F, Detmar M, Goetinck P . Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4 . J. Clin. Invest. . 107 . 2 . R9–R14 . January 2001 . 11160142 . 199172 . 10.1172/JCI10559 .
16. Chelariu-Raicu . Anca . Wilke . Cornelia . Brand . Melanie . Starzinski-Powitz . Anna . Kiesel . Ludwig . Schüring . Andreas N . Götte . Martin . Syndecan-4 expression is upregulated in endometriosis and contributes to an invasive phenotype. . Fertility and Sterility . 2016 . 106 . 2 . 378–85 . 10.1016/j.fertnstert.2016.03.032 . 27041028 . free .
17. Hass MJ . Sep 2009 . SDC4: OA joint effort . SciBX . 2 . 34. 1297. 10.1038/scibx.2009.1297 . free .