S-Nitrosylation of Matrix Metalloproteinases: Signaling Pathway to Neuronal Cell Death

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Science  16 Aug 2002:
Vol. 297, Issue 5584, pp. 1186-1190
DOI: 10.1126/science.1073634

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Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of neurodegenerative diseases and stroke. However, the mechanism of MMP activation remains unclear. We report that MMP activation involves S-nitrosylation. During cerebral ischemia in vivo, MMP-9 colocalized with neuronal nitric oxide synthase. S-Nitrosylation activated MMP-9 in vitro and induced neuronal apoptosis. Mass spectrometry identified the active derivative of MMP-9, both in vitro and in vivo, as a stable sulfinic or sulfonic acid, whose formation was triggered by S-nitrosylation. These findings suggest a potential extracellular proteolysis pathway to neuronal cell death in which S-nitrosylation activates MMPs, and further oxidation results in a stable posttranslational modification with pathological activity.

  • * These authors contributed equally to this work.

  • To whom correspondence should be addressed. E-mail: slipton{at}

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