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

GA McQuibban, JH Gong, EM Tam, CAG McCulloch… - Science, 2000 - science.org
GA McQuibban, JH Gong, EM Tam, CAG McCulloch, I Clark-Lewis, CM Overall
Science, 2000science.org
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 …
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.
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