Syndecan-4 is a protein that in humans is encoded by the SDC4gene.[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]
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 syndecanproteoglycan 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
Osteoarthritis
Syndecan-4 is upregulated in osteoarthritis and inhibition of syndecan-4 reduces cartilage destruction in mouse models of OA.[16]
↑Kojima T, Inazawa J, Takamatsu J, Rosenberg RD, Saito H (Mar 1993). "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. doi:10.1006/bbrc.1993.1122. PMID7916598.
↑Hyatt SL, Klauck T, Jaken S (1990). "Protein kinase C is localized in focal contacts of normal but not transformed fibroblasts". Mol. Carcinog. 3 (2): 45–53. doi:10.1002/mc.2940030202. PMID2161238.
↑Oh ES, Woods A, Couchman JR (May 1997). "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. doi:10.1074/jbc.272.18.11805. PMID9115237.
↑Chua CC, Rahimi N, Forsten-Williams K, Nugent MA (February 2004). "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. doi:10.1161/01.RES.0000112965.70691.AC. PMID14684627.
↑Olsson U, Bondjers G, Camejo G (March 1999). "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. doi:10.2337/diabetes.48.3.616. PMID10078565.
Yu H, Humphries DE, Watkins M, Karlinsky JB (1995). "Molecular cloning of the human ryudocan promoter". Biochem. Biophys. Res. Commun. 212 (3): 1139–44. doi:10.1006/bbrc.1995.2087. PMID7626103.
Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Albini A, Benelli R, Presta M, Rusnati M, Ziche M, Rubartelli A, Paglialunga G, Bussolino F, Noonan D (1996). "HIV-tat protein is a heparin-binding angiogenic growth factor". Oncogene. 12 (2): 289–97. PMID8570206.
Kojima T, Katsumi A, Yamazaki T, Muramatsu T, Nagasaka T, Ohsumi K, Saito H (1996). "Human ryudocan from endothelium-like cells binds basic fibroblast growth factor, midkine, and tissue factor pathway inhibitor". J. Biol. Chem. 271 (10): 5914–20. doi:10.1074/jbc.271.10.5914. PMID8621465.
Takagi A, Kojima T, Tsuzuki S, Katsumi A, Yamazaki T, Sugiura I, Hamaguchi M, Saito H (1997). "Structural organization and promoter activity of the human ryudocan gene". J. Biochem. 119 (5): 979–84. doi:10.1093/oxfordjournals.jbchem.a021338. PMID8797100.
Rusnati M, Coltrini D, Oreste P, Zoppetti G, Albini A, Noonan D, d'Adda di Fagagna F, Giacca M, Presta M (1997). "Interaction of HIV-1 Tat protein with heparin. Role of the backbone structure, sulfation, and size". J. Biol. Chem. 272 (17): 11313–20. doi:10.1074/jbc.272.17.11313. PMID9111037.
Chang HC, Samaniego F, Nair BC, Buonaguro L, Ensoli B (1997). "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. doi:10.1097/00002030-199712000-00006. PMID9342064.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Horowitz A, Simons M (1998). "Regulation of syndecan-4 phosphorylation in vivo". J. Biol. Chem. 273 (18): 10914–8. doi:10.1074/jbc.273.18.10914. PMID9556568.
Lee D, Oh ES, Woods A, Couchman JR, Lee W (1998). "Solution structure of a syndecan-4 cytoplasmic domain and its interaction with phosphatidylinositol 4,5-bisphosphate". J. Biol. Chem. 273 (21): 13022–9. doi:10.1074/jbc.273.21.13022. PMID9582338.
Rusnati M, Tulipano G, Spillmann D, Tanghetti E, Oreste P, Zoppetti G, Giacca M, Presta M (1999). "Multiple interactions of HIV-I Tat protein with size-defined heparin oligosaccharides". J. Biol. Chem. 274 (40): 28198–205. doi:10.1074/jbc.274.40.28198. PMID10497173.
Tyagi M, Rusnati M, Presta M, Giacca M (2001). "Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans". J. Biol. Chem. 276 (5): 3254–61. doi:10.1074/jbc.M006701200. PMID11024024.
Shin J, Lee W, Lee D, Koo BK, Han I, Lim Y, Woods A, Couchman JR, Oh ES (2001). "Solution structure of the dimeric cytoplasmic domain of syndecan-4". Biochemistry. 40 (29): 8471–8. doi:10.1021/bi002750r. PMID11456484.
