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.
McQuibban
G A
GA
Department of Biochemistry and Molecular Biology, Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Gong
J H
JH
Tam
E M
EM
McCulloch
C A
CA
Clark-Lewis
I
I
Overall
C M
CM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020134:Catalytic Domain; D002460:Cell Line; D054410:Chemokine CCL7; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003094:Collagen / Q000378:metabolism; D016207:Cytokines; D004789:Enzyme Activation; D015723:Gene Library; D006466:Hemopexin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D013058:Mass Spectrometry; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D020798:Two-Hybrid System Techniques
C515450:CCL7 protein, human; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D018925:Chemokines; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D006466:Hemopexin; D020778:Matrix Metalloproteinase 2; D002118:Calcium