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Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3.

Tissue degradation by the matrix metalloproteinase gelatinase A is pivotal to inflammation and metastases. Recognizing the catalytic importance of substrate-binding exosites outside the catalytic domain, we screened for extracellular substrates using the gelatinase A hemopexin domain as bait in the yeast two-hybrid system. Monocyte chemoattractant protein-3 (MCP-3) was identified as a physiological substrate of gelatinase A. Cleaved MCP-3 binds to CC-chemokine receptors-1, -2, and -3, but no longer induces calcium fluxes or promotes chemotaxis, and instead acts as a general chemokine antagonist that dampens inflammation. This suggests that matrix metalloproteinases are both effectors and regulators of the inflammatory response.

Pubmed ID: 10947989

Authors

  • McQuibban GA
  • Gong JH
  • Tam EM
  • McCulloch CA
  • Clark-Lewis I
  • Overall CM

Journal

Science (New York, N.Y.)

Publication Data

August 18, 2000

Associated Grants

None

Mesh Terms

  • Animals
  • Calcium
  • Catalytic Domain
  • Cell Line
  • Chemokine CCL7
  • Chemokines
  • Chemotaxis, Leukocyte
  • Collagen
  • Cytokines
  • Enzyme Activation
  • Gene Library
  • Hemopexin
  • Humans
  • Inflammation
  • Mass Spectrometry
  • Matrix Metalloproteinase 2
  • Mice
  • Monocyte Chemoattractant Proteins
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Chemokine
  • Recombinant Proteins
  • Tissue Inhibitor of Metalloproteinase-2
  • Two-Hybrid System Techniques