Abstract
Membrane-bound proteoglycans function primarily as coreceptors for many glycosaminoglycan (GAG)-binding ligands at the cell surface. The majority of membrane-bound proteoglycans can also function as soluble autocrine or paracrine effectors as their extracellular domains, replete with all GAG chains, are enzymatically cleaved and released from the cell surface by ectodomain shedding. In particular, the ectodomain shedding of syndecans, a major family of cell surface heparan sulfate proteoglycans, is an important posttranslational mechanism that modulates diverse pathophysiological processes. Syndecan shedding is a tightly controlled process that regulates the onset, progression, and resolution of various infectious and noninfectious inflammatory diseases. This review describes methods to induce and measure the shedding of cell membrane-bound proteoglycans, focusing on syndecan shedding as a prototypic example.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bernfield, M., Götte, M., Park, P. W., Reizes, O., Fitzgerald, M. L., Lincecum, J., and Zako, M. (1999) Functions of cell surface heparan sulfate proteoglycans, Annu. Rev. Biochem. 68, 729–777.
Couchman, J. R. (2010) Transmembrane Signaling Proteoglycans, Annu Rev Cell Dev Biol., 26, 89–114.
Park, P. W., Reizes, O., and Bernfield, M. (2000) Cell surface heparan sulfate proteoglycans: selective regulators of ligand-receptor encounters, J. Biol. Chem. 275, 29923–29926.
Hayashida, K., Bartlett, A. H., Chen, Y., and Park, P. W. (2010) Molecular and cellular mechanisms of ectodomain shedding, Anat. Rec. 293, 925–937.
Steppan, J., Hofer, S., Funke, B., Brenner, T., Henrich, M., Martin, E., et al. (2011) Sepsis and Major Abdominal Surgery Lead to Flaking of the Endothelial Glycocalix, J Surg Res, 165, 136–141.
Nelson, A., Berkestedt, I., Schmidtchen, A., Ljunggren, L., and Bodelsson, M. (2008) Increased levels of glycosaminoglycans during septic shock: relation to mortality and the antibacterial actions of plasma, Shock 30, 623–627.
Rehm, M., Bruegger, D., Christ, F., Conzen, P., Thiel, M., Jacob, M., et al. (2007) Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia, Circulation 116, 1896–1906.
Seidel, C., Ringdén, O., and Remberger, M. (2003) Increased levels of syndecan-1 in serum during acute graft-versus-host disease, Transplantation 76, 423–426.
Joensuu, H., Anttonen, A., Eriksson, M., Makitaro, R., Alfthan, H., Kinnula, V., and Leppa, S. (2002) Soluble syndecan-1 and serum basic fibroblast growth factor are new prognostic factors in lung cancer, Cancer Res. 62, 5210–5217.
Yang, Y., Yaccoby, S., Liu, W., Langford, J. K., Pumphrey, C. Y., Theus, A., et al. (2002) Soluble syndecan-1 promotes growth of myeloma tumors in vivo, Blood 100, 610–617.
Kainulainen, V., Wang, H., Schick, C., and Bernfield, M. (1998) Syndecans, heparan sulfate proteoglycans, maintain the proteolytic balance of acute wound fluids, J. Biol. Chem. 273, 11563–11569.
Kliment, C. R., Englert, J. M., Gochuico, B. R., Yu, G., Kaminski, N., Rosas, I., and Oury, T. D. (2009) Oxidative stress alters syndecan-1 distribution in lungs with pulmonary fibrosis, J Biol Chem 284, 3537–3545.
Kato, M., Wang, H., Kainulainen, V., Fitzgerald, M. L., Ledbetter, S., Ornitz, D. M., and Bernfield, M. (1998) Physiological degradation converts the soluble syndecan-1 ectodomain from an inhibitor to a potent activator of FGF-2, Nat. Med. 4, 691–697.
Li, Q., Park, P. W., Wilson, C. L., and Parks, W. C. (2002) Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury, Cell 111, 635–646.
Xu, J., Park, P. W., Kheradmand, F., and Corry, D. B. (2005) Endogenous attenuation of allergic lung inflammation by syndecan-1, J. Immunol. 174, 5758–5765.
Park, P. W., Pier, G. B., Hinkes, M. T., and Bernfield, M. (2001) Exploitation of syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence, Nature 411, 98–102.
Hayashida, A., Bartlett, A. H., Foster, T. J., and Park, P. W. (2009) Staphylococcus aureus beta-toxin induces acute lung injury through syndecan-1, Am. J. Pathol. 174, 509–518.
Hayashida, K., Parks, W. C., and Park, P. W. (2009) Syndecan-1 shedding facilitates the resolution of neutrophilic inflammation by removing sequestered CXC chemokines, Blood 114, 3033–3043.
Hayashida, K., Chen, Y., Bartlett, A. H., and Park, P. W. (2008) Syndecan-1 is an in vivo suppressor of Gram-positive toxic shock, J. Biol. Chem. 283, 19895–19903.
Katoh, S., Taniguchi, H., Matsubara, Y., Matsumoto, N., Fukushima, K., Kadota, J., et al. (1999) Overexpression of CD44 on alveolar eosinophils with high concentrations of soluble CD44 in bronchoalveolar lavage fluid in patients with eosinophilic pneumonia, Allergy 54, 1286–1292.
Wang, Q., Teder, P., Judd, N. P., Noble, P. W., and Doerschuk, C. M. (2002) CD44 deficiency leads to enhanced neutrophil migration and lung injury in Escherichia coli pneumonia in mice, Am. J. Pathol. 161, 2219–2228.
Kim, C. W., Goldberger, O. A., Gallo, R. L., and Bernfield, M. (1994) Members of the syndecan family of heparan sulfate proteoglycans are expressed in distinct cell-, tissue-, and development-specific patterns, Mol. Biol. Cell 5, 797–805.
Chen, Y., Bennett, A., Hayashida, A., Hollingshead, S., and Park, P. W. (2007) Streptococcus pneumoniae sheds syndecan-1 ectodomains via ZmpC, a metalloproteinase virulence factor, J. Biol. Chem. 282, 159–167.
Fitzgerald, M. L., Wang, Z., Park, P. W., Murphy, G., and Bernfield, M. (2000) Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3 sensitive metalloproteinase, J. Cell Biol. 148, 811–824.
Hayashida, K., Stahl, P. D., and Park, P. W. (2008) Syndecan-1 ectodomain shedding is regulated by the small GTPase Rab5, J. Biol. Chem. 283, 35435–35444.
Park, P. W., Foster, T. J., Nishi, E., Duncan, S. J., Klagsbrun, M., and Chen, Y. (2004) Activation of syndecan-1 ectodomain shedding by Staphylococcus aureus alpha-toxin and beta-toxin, J. Biol. Chem. 279, 251–258.
Park, P. W., Pier, G. B., Preston, M. J., Goldberger, O., Fitzgerald, M. L., and Bernfield, M. (2000) Syndecan-1 shedding is enhanced by LasA, a secreted virulence factor of Pseudomonas aeruginosa, J. Biol. Chem. 275, 3057–3064.
Popova, T. G., Millis, B., Bradburne, C., Nazarenko, S., Bailey, C., Chandhoke, V., and Popov, S. G. (2006) Acceleration of epithelial cell syndecan-1 shedding by anthrax hemolytic virulence factors, BMC Microbiol. 6, 8–24.
Subramanian, S. V., Fitzgerald, M. L., and Bernfield, M. (1997) Regulated shedding of syndecan-1 and -4 ectodomains by thrombin and growth factor activation, J. Biol. Chem. 272, 14713-14720.
Yang, Y., Macleod, V., Miao, H. Q., Theus, A., Zhan, F., Shaughnessy, J. D. Jr., et al. (2007) Heparanase enhances syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis, J. Biol. Chem. 282, 13326–13333.
Hayashida, K., Johnston, D. R., Goldberger, O., and Park, P. W. (2006) Syndecan-1 expression in epithelial cells is induced by TGF-beta through a PKA-dependent pathway, J. Biol. Chem. 281, 24365–24374.
Ding, K., Lopez-Burks, M., Sanchez-Duran, J. A., Korc, M., and Lander, A. D. (2005) Growth factor-induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells, J. Cell Biol. 171, 729–738.
Reizes, O., Goldberger, O., Smith, A. C., Xu, Z., Bernfield, M., and Bickel, P. E. (2006) Insulin promotes shedding of syndecan ectodomains from 3T3-L1 adipocytes: a proposed mechanism for stabilization of extracellular lipoprotein lipase, Biochemistry 45, 5703–5711.
Day, R. M., Mitchell, T. J., Knight, S. C., and Forbes, A. (2003) Regulation of epithelial syndecan-1 expression by inflammatory cytokines, Cytokine 21, 224–233.
Henry-Stanley, M. J., Zhang, B., Erlandsen, S. L., and Wells, C. L. (2006) Synergistic effect of tumor necrosis factor-alpha and interferon-gamma on enterocyte shedding of syndecan-1 and associated decreases in internalization of Listeria monocytogenes and Staphylococcus aureus, Cytokine 34, 252–259.
Charnaux, N., Brule, S., Chaigneau, T., Saffar, L., Sutton, A., Hamon, M., et al. (2005) RANTES (CCL5) induces a CCR5-dependent accelerated shedding of syndecan-1 (CD138) and syndecan-4 from HeLa cells and forms complexes with the shed ectodomains of these proteoglycans as well as with those of CD44, Glycobiology 15, 119–130.
Brule, S., Charnaux, N., Sutton, A., Ledoux, D., Chaigneau, T., Saffar, L., and Gattegno, L. (2006) The shedding of syndecan-4 and syndecan-1 from HeLa cells and human primary macrophages is accelerated by SDF-1/CXCL12 and mediated by the matrix metalloproteinase-9, Glycobiology 16, 488–501.
Endo, K., Takino, T., Miyamori, H., Kinsen, H., Yoshizaki, T., Furukawa, M., and Sato, H. (2003) Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration, J. Biol. Chem. 278, 40764–40770.
Pruessmeyer, J., Martin, C., Hess, F. M., Schwarz, N., Schmidt, S., Kogel, T., et al. (2010) A disintegrin and metalloproteinase 17 (ADAM17) mediates inflammation-induced shedding of syndecan-1 and -4 by lung epithelial cells, J Biol Chem 285, 555–564.
Chung, M. C., Popova, T. G., Millis, B. A., Mukherjee, D. V., Zhou, W., Liotta, L. A., et al. (2006) Secreted neutral metalloproteases of Bacillus anthracis as candidate pathogenic factors, J. Biol. Chem. 281, 31408–31418.
Acknowledgments
The authors would like to thank past and present members of the Park laboratory for developing essential reagents and constantly improving the described procedures. This work was supported by NIH grants R01 HL094613 and R01 HL107472.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Nam, E.J., Park, P.W. (2012). Shedding of Cell Membrane-Bound Proteoglycans. In: Rédini, F. (eds) Proteoglycans. Methods in Molecular Biology, vol 836. Humana Press. https://doi.org/10.1007/978-1-61779-498-8_19
Download citation
DOI: https://doi.org/10.1007/978-1-61779-498-8_19
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-61779-497-1
Online ISBN: 978-1-61779-498-8
eBook Packages: Springer Protocols