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tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2.

Publication ,  Journal Article
Nolin, WB; Emmetsberger, J; Bukhari, N; Zhang, Y; Levine, JM; Tsirka, SE
Published in: Glia
January 15, 2008

Paralysis resulting from spinal cord injury is devastating and persistent. One major reason for the inability of the body to heal this type of injury ensues from the local increase of glial cells leading to the formation of a glial scar, and the upregulation of chondroitin sulfate proteoglycans (CSPGs) at the site of injury through which axons are unable to regenerate. Experimental approaches to overcome this problem have accordingly focused on reducing the inhibitory properties of CSPGs, for example by using chondroitinase to remove the sugar chains and reduce the CSPGs to their core protein constituents, although this step alone does not provide dramatic benefits as a monotherapy. Using in vitro and in vivo approaches, we describe here a potentially synergistic therapeutic opportunity based on tissue plasminogen activator (tPA), an extracellular protease that converts plasminogen (plg) into the active protease plasmin. We show that tPA and plg both bind to the CSPG protein NG2, which functions as a scaffold to accelerate the tPA-driven conversion of plg to plasmin. The binding occurs via the tPA and plg kringle domains to domain 2 of the NG2 CSPG core protein, and is enhanced in some settings after chondroitinase-mediated removal of the NG2 proteoglycan side chains. Once generated, plasmin then degrades NG2, both in an in vitro setting using recombinant protein, and in vivo models of spinal cord injury. Our finding that the tPA and plg binding is in some instances more efficient after exposure of the NG2 proteoglycan to chondroitinase treatment suggests that a combined therapeutic approach employing both chondroitinase and the tPA/plasmin proteolytic system could be of significant benefit in promoting axonal regeneration through glial scars after spinal cord injury.

Duke Scholars

Published In

Glia

DOI

ISSN

0894-1491

Publication Date

January 15, 2008

Volume

56

Issue

2

Start / End Page

177 / 189

Location

United States

Related Subject Headings

  • UDP Xylose-Protein Xylosyltransferase
  • Tissue Plasminogen Activator
  • Time Factors
  • Spinal Cord Injuries
  • Silver Staining
  • Recombinant Fusion Proteins
  • Proteoglycans
  • Protein Structure, Tertiary
  • Protein Binding
  • Pentosyltransferases
 

Citation

APA
Chicago
ICMJE
MLA
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Nolin, W. B., Emmetsberger, J., Bukhari, N., Zhang, Y., Levine, J. M., & Tsirka, S. E. (2008). tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2. Glia, 56(2), 177–189. https://doi.org/10.1002/glia.20603
Nolin, Westley B., Jaime Emmetsberger, Noreen Bukhari, Yan Zhang, Joel M. Levine, and Stella E. Tsirka. “tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2.Glia 56, no. 2 (January 15, 2008): 177–89. https://doi.org/10.1002/glia.20603.
Nolin WB, Emmetsberger J, Bukhari N, Zhang Y, Levine JM, Tsirka SE. tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2. Glia. 2008 Jan 15;56(2):177–89.
Nolin, Westley B., et al. “tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2.Glia, vol. 56, no. 2, Jan. 2008, pp. 177–89. Pubmed, doi:10.1002/glia.20603.
Nolin WB, Emmetsberger J, Bukhari N, Zhang Y, Levine JM, Tsirka SE. tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2. Glia. 2008 Jan 15;56(2):177–189.
Journal cover image

Published In

Glia

DOI

ISSN

0894-1491

Publication Date

January 15, 2008

Volume

56

Issue

2

Start / End Page

177 / 189

Location

United States

Related Subject Headings

  • UDP Xylose-Protein Xylosyltransferase
  • Tissue Plasminogen Activator
  • Time Factors
  • Spinal Cord Injuries
  • Silver Staining
  • Recombinant Fusion Proteins
  • Proteoglycans
  • Protein Structure, Tertiary
  • Protein Binding
  • Pentosyltransferases