SDC4

Syndecan 4
PDB rendering based on 1ejp.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1EJP​, 1EJQ​, 1OBY​, 1YBO​
Identifiers
Symbols	SDC4 ; SYND4
External IDs	OMIM: 600017 MGI: 1349164 HomoloGene: 31121 GeneCards: SDC4 Gene
Gene ontology Molecular function • fibronectin binding • protein kinase C binding • protein binding • thrombospondin receptor activity Cellular component • Golgi lumen • plasma membrane • integral component of plasma membrane • focal adhesion • cell surface • costamere • lysosomal lumen • membrane raft • extracellular exosome Biological process • retinoid metabolic process • ureteric bud development • neural tube closure • carbohydrate metabolic process • glycosaminoglycan biosynthetic process • glycosaminoglycan catabolic process • phototransduction, visible light • regulation of fibroblast migration • cell migration • extracellular matrix organization • glycosaminoglycan metabolic process • chondroitin sulfate metabolic process • wound healing • small molecule metabolic process • positive regulation of protein kinase activity • positive regulation of stress fiber assembly • positive regulation of focal adhesion assembly • inner ear receptor stereocilium organization • positive regulation of exosomal secretion • positive regulation of extracellular exosome assembly Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6385	20971
Ensembl	ENSG00000124145	ENSMUSG00000017009
UniProt	P31431	O35988
RefSeq (mRNA)	NM_002999	NM_011521
RefSeq (protein)	NP_002990	NP_035651
Location (UCSC)	Chr 20: 45.33 – 45.35 Mb	Chr 2: 164.42 – 164.44 Mb
PubMed search

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

Osteoarthritis

Syndecan-4 is upregulated in osteoarthritis and inhibition of syndecan-4 reduces cartilage destruction in mouse models of OA.^[16]

See Sindecán-4 at the Spanish Wikipedia

References

1. 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. PMID 7916598.
2. David G, van der Schueren B, Marynen P, Cassiman JJ, van den Berghe H (Sep 1992). "Molecular cloning of amphiglycan, a novel integral membrane heparan sulfate proteoglycan expressed by epithelial and fibroblastic cells". J Cell Biol 118 (4): 961–9. doi:10.1083/jcb.118.4.961. PMC 2289559. PMID 1500433.
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. doi:10.1091/mbc.5.2.183. PMC 301024. PMID 8019004.
4. "Entrez Gene: SDC4 syndecan 4".
5. Woods A, Couchman JR (February 1994). "Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component". Mol. Biol. Cell 5 (2): 183–92. doi:10.1091/mbc.5.2.183. PMC 301024. PMID 8019004.
6. Woods A, Couchman JR (May 1998). "Syndecans: synergistic activators of cell adhesion". Trends Cell Biol. 8 (5): 189–92. doi:10.1016/S0962-8924(98)01244-6. PMID 9695837.
7. 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. PMID 2161238.
8. Grootjans JJ, Zimmermann P, Reekmans G, Smets A, Degeest G, Dürr J, David G (December 1997). "Syntenin, a PDZ protein that binds syndecan cytoplasmic domains". Proc. Natl. Acad. Sci. U.S.A. 94 (25): 13683–8. Bibcode:1997PNAS...9413683G. doi:10.1073/pnas.94.25.13683. PMC 28366. PMID 9391086.
9. 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. PMID 9115237.
10. 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. PMID 14684627.
11. Bortoff KD, Wagner WD (February 2005). "Reduced syndecan-4 expression in arterial smooth muscle cells with enhanced proliferation". Exp. Mol. Pathol. 78 (1): 10–6. doi:10.1016/j.yexmp.2004.08.010. PMID 15596055.
12. Neelapu SS, Gause BL, Harvey L, Lee ST, Frye AR, Horton J, Robb RJ, Popescu MC, Kwak LW (June 2007). "A novel proteoliposomal vaccine induces antitumor immunity against follicular lymphoma". Blood 109 (12): 5160–3. doi:10.1182/blood-2006-12-063594. PMC 1941785. PMID 17339422.
13. 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. PMID 10078565.
14. Jang E, Albadawi H, Watkins MT, Edelman ER, Baker AB (January 2012). "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. Bibcode:2012PNAS..109.1679J. doi:10.1073/pnas.1117885109. PMC 3277125. PMID 22307630.
15. Echtermeyer F, Streit M, Wilcox-Adelman S, Saoncella S, Denhez F, Detmar M, Goetinck P (January 2001). "Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4". J. Clin. Invest. 107 (2): R9–R14. doi:10.1172/JCI10559. PMC 199172. PMID 11160142.
16. Hass MJ (Sep 2009). "SDC4: OA joint effort". SciBX 2 (34). doi:10.1038/scibx.2009.1297.

Further reading

• Bass MD, Humphries MJ (2002). "Cytoplasmic interactions of syndecan-4 orchestrate adhesion receptor and growth factor receptor signalling". Biochem. J. 368 (Pt 1): 1–15. doi:10.1042/BJ20021228. PMC 1222989. PMID 12241528.
• 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. PMID 7626103.
• Barillari G, Gendelman R, Gallo RC, Ensoli B (1993). "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. Bibcode:1993PNAS...90.7941B. doi:10.1073/pnas.90.17.7941. PMC 47263. PMID 7690138.
• Woods A, Couchman JR (1994). "Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component". Mol. Biol. Cell 5 (2): 183–92. doi:10.1091/mbc.5.2.183. PMC 301024. PMID 8019004.
• 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. PMID 8125298.
• 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. PMID 8570206.
• 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. PMID 8621465.
• 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. PMID 8797100.
• 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. PMID 9111037.
• 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. PMID 9342064.
• 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. PMID 9373149.
• 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. PMID 9556568.
• 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. PMID 9582338.
• Cohen AR, Woods DF, Marfatia SM, Walther Z, Chishti AH, Anderson JM (1998). "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. doi:10.1083/jcb.142.1.129. PMC 2133028. PMID 9660868.
• 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. PMID 10497173.
• Gao Y, Li M, Chen W, Simons M (2000). "Synectin, syndecan-4 cytoplasmic domain binding PDZ protein, inhibits cell migration". J. Cell. Physiol. 184 (3): 373–9. doi:10.1002/1097-4652(200009)184:3<373::AID-JCP12>3.0.CO;2-I. PMID 10911369.
• 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. PMID 11024024.
• 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. PMID 11456484.