Biology:Syndecan-4

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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

References

  1. ↑ "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. doi:10.1006/bbrc.1993.1122. PMID 7916598. 
  2. ↑ "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. doi:10.1083/jcb.118.4.961. PMID 1500433. 
  3. ↑ "Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component". Mol Biol Cell 5 (2): 183–192. 1994. doi:10.1091/mbc.5.2.183. PMID 8019004. 
  4. ↑ 4.0 4.1 "Entrez Gene: SDC4 syndecan 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6385. 
  5. ↑ "Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component". Mol. Biol. Cell 5 (2): 183–92. February 1994. doi:10.1091/mbc.5.2.183. PMID 8019004. 
  6. ↑ "Syndecans: synergistic activators of cell adhesion". Trends Cell Biol. 8 (5): 189–92. May 1998. doi:10.1016/S0962-8924(98)01244-6. PMID 9695837. 
  7. ↑ "Protein kinase C is localized in focal contacts of normal but not transformed fibroblasts". Mol. Carcinog. 3 (2): 45–53. 1990. doi:10.1002/mc.2940030202. PMID 2161238. 
  8. ↑ "Syntenin, a PDZ protein that binds syndecan cytoplasmic domains". Proc. Natl. Acad. Sci. U.S.A. 94 (25): 13683–8. December 1997. doi:10.1073/pnas.94.25.13683. PMID 9391086. Bibcode: 1997PNAS...9413683G. 
  9. ↑ "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. doi:10.1074/jbc.272.18.11805. PMID 9115237. 
  10. ↑ "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. doi:10.1161/01.RES.0000112965.70691.AC. PMID 14684627. 
  11. ↑ "Reduced syndecan-4 expression in arterial smooth muscle cells with enhanced proliferation". Exp. Mol. Pathol. 78 (1): 10–6. February 2005. doi:10.1016/j.yexmp.2004.08.010. PMID 15596055. 
  12. ↑ "A novel proteoliposomal vaccine induces antitumor immunity against follicular lymphoma". Blood 109 (12): 5160–3. June 2007. doi:10.1182/blood-2006-12-063594. PMID 17339422. 
  13. ↑ "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. doi:10.2337/diabetes.48.3.616. PMID 10078565. 
  14. ↑ "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. doi:10.1073/pnas.1117885109. PMID 22307630. Bibcode: 2012PNAS..109.1679J. 
  15. ↑ "Delayed wound repair and impaired angiogenesis in mice lacking syndecan-4". J. Clin. Invest. 107 (2): R9–R14. January 2001. doi:10.1172/JCI10559. PMID 11160142. 
  16. ↑ Chelariu-Raicu, Anca; Wilke, Cornelia; Brand, Melanie; Starzinski-Powitz, Anna; Kiesel, Ludwig; Schüring, Andreas N; Götte, Martin (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. 
  17. ↑ Hass MJ (Sep 2009). "SDC4: OA joint effort". SciBX 2 (34): 1297. doi:10.1038/scibx.2009.1297. 

Further reading

External links




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