Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium / metabolism
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Catalytic Domain
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Cell Line
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Chemokine CCL7
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Chemokines / antagonists & inhibitors
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Chemokines / metabolism
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Chemotaxis, Leukocyte
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Collagen / metabolism
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Cytokines*
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Enzyme Activation
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Gene Library
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Hemopexin / chemistry
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Hemopexin / metabolism
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Humans
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Inflammation / metabolism*
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Inflammation / pathology
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Mass Spectrometry
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Matrix Metalloproteinase 2 / chemistry
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Matrix Metalloproteinase 2 / metabolism*
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Mice
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Monocyte Chemoattractant Proteins / metabolism*
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Protein Binding
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Protein Structure, Tertiary
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Receptors, Chemokine / antagonists & inhibitors
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Receptors, Chemokine / metabolism
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Recombinant Proteins / metabolism
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Tissue Inhibitor of Metalloproteinase-2 / metabolism
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Two-Hybrid System Techniques
Substances
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CCL7 protein, human
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Ccl7 protein, mouse
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Chemokine CCL7
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Chemokines
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Cytokines
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Monocyte Chemoattractant Proteins
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Receptors, Chemokine
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Recombinant Proteins
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Tissue Inhibitor of Metalloproteinase-2
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Collagen
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Hemopexin
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Matrix Metalloproteinase 2
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Calcium