Syndecan-4

SDC4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1EJP, 1EJQ, 1OBY, 1YBO
Identifiers
Aliases	SDC4 , SYND4, syndecan 4
External IDs	OMIM: 600017; MGI: 1349164; HomoloGene: 31121; GeneCards: SDC4; OMA:SDC4 - orthologs
Gene location (Human) Chr. Chromosome 20 (human) [1] Band 20q13.12 Start 45,325,288 bp [1] End 45,348,424 bp [1]
Gene location (Mouse) Chr. Chromosome 2 (mouse) [2] Band 2 H3|2 85.16 cM Start 164,266,167 bp [2] End 164,285,807 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in olfactory zone of nasal mucosa nasal epithelium cartilage tissue beta cell epithelium of bronchus bronchial epithelial cell skin of abdomen skin of leg external globus pallidus human kidney Top expressed in vestibular membrane of cochlear duct gallbladder lacrimal gland blastocyst ciliary body utricle ascending aorta left lobe of liver superior surface of tongue aortic valve More reference expression data BioGPS More reference expression data
Gene ontology Molecular function fibronectin binding protein binding thrombospondin receptor activity protein kinase C binding identical protein binding Cellular component integral component of membrane membrane focal adhesion plasma membrane integral component of plasma membrane extracellular region lysosomal lumen Golgi lumen membrane raft costamere extracellular exosome cell surface Biological process glycosaminoglycan metabolic process ureteric bud development inner ear receptor cell stereocilium organization positive regulation of extracellular exosome assembly wound healing retinoid metabolic process neural tube closure glycosaminoglycan catabolic process glycosaminoglycan biosynthetic process positive regulation of focal adhesion assembly positive regulation of exosomal secretion regulation of fibroblast migration positive regulation of stress fiber assembly positive regulation of protein kinase activity signal transduction negative regulation of T cell proliferation leukocyte migration cell migration Sources:Amigo / QuickGO
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: 164.27 – 164.29 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Syndecan-4 is a protein that in humans is encoded by the SDC4 gene. ^{[5] [6]} 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. ^[7]

Gene

Syndecan-4 is also called ryudocan or amphiglycan. It is found on chromosome 20, while a pseudogene has been found on chromosome 22. ^[8] 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. ^[9]

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. ^[8] Syndecan-4 interacts with extracellular matrix, anticoagulants, and growth-factors. It also regulates the actin cytoskeleton, cell adhesion, and cell migration. ^[10]

Syndecan-4 activates protein kinase C (PKC), an enzyme involved in signal transduction. ^[11] 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. ^[12] Syndecan-4 also binds to phosphatidylinositol (4,5)-bisphosphate (PIP2) through the variable domain and increases PKC activity ten-fold. ^[13]

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. ^[14] 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. ^{[15] [16] [17]} 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. ^[18]

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. ^[19]

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. ^[20]

Osteoarthritis

Syndecan-4 is upregulated in osteoarthritis and inhibition of syndecan-4 reduces cartilage destruction in mouse models of OA. ^[21]

See Sindecán-4 at the Spanish Wikipedia

References

1. GRCh38: Ensembl release 89: ENSG00000124145 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000017009 – 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. 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.
6. 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.
7. 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.
8. "Entrez Gene: SDC4 syndecan 4".
9. 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.
10. 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.
11. 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. S2CID   46254921.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. Chelariu-Raicu A, Wilke C, Brand M, Starzinski-Powitz A, Kiesel L, Schüring AN, Götte M (2016). "Syndecan-4 expression is upregulated in endometriosis and contributes to an invasive phenotype". Fertility and Sterility. 106 (2): 378–85. doi: 10.1016/j.fertnstert.2016.03.032 . PMID   27041028.
21. Hass MJ (Sep 2009). "SDC4: OA joint effort". SciBX. 2 (34): 1297. 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. S2CID   7648619.
• 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. S2CID   20829740.
• 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.

External links

• Overview of all the structural information available in the PDB for UniProt : P31431 (Syndecan-4) at the PDBe-KB .