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...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) Vol. 289; no. 5482; pp. 1202 - 1206
Main Authors:	McQuibban, G. Angus, Gong, Jiang-Hong, Tam, Eric M., Christopher A. G. Mc Culloch, Clark-Lewis, Ian, Overall, Christopher M.
Format:	Journal Article
Language:	English
Published:	Washington, DC American Society for the Advancement of Science 18-08-2000 American Association for the Advancement of Science The American Association for the Advancement of Science
Subjects:	Animals Antibodies Aspartic proteases Aspartic proteinases Biochemistry Biological and medical sciences Calcium Calcium - metabolism Catalytic Domain CCR protein CCR1 protein CCR2 protein CCR3 protein Cell Line Cell lines Chemokine CCL7 Chemokines Chemokines - antagonists & inhibitors Chemokines - metabolism Chemotaxis, Leukocyte Collagen - metabolism Cytokines Enzyme Activation Epithelial cells Fundamental and applied biological sciences. Psychology Gene Library Hemopexin - chemistry Hemopexin - metabolism Humans Inflammation Inflammation - metabolism Inflammation - pathology Leukocytes Libraries Mass Spectrometry Matrix Metalloproteinase 2 - chemistry Matrix Metalloproteinase 2 - metabolism Mice Molecular and cellular biology monocyte chemoattractant protein 3 Monocyte Chemoattractant Proteins - metabolism Monocytes Protein Binding Protein Structure, Tertiary Proteins Receptors, Chemokine - antagonists & inhibitors Receptors, Chemokine - metabolism Recombinant Proteins - metabolism Tissue Inhibitor of Metalloproteinase-2 - metabolism Two-Hybrid System Techniques Visual stimulation Yeast Yeasts Human Enzyme Cytokine Metalloendopeptidases Inflammation Chemotaxis Gelatinase A Degradation Substrate Peptidases Regulation(control) Hydrolases Extracellular matrix
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.289.5482.1202