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Science 297 (5584): 1186-1190

Copyright © 2002 by the American Association for the Advancement of Science

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

Zezong Gu,1 Marcus Kaul,1 Boxu Yan,2* Steven J. Kridel,2* Jiankun Cui,1 Alex Strongin,2 Jeffrey W. Smith,2 Robert C. Liddington,2 Stuart A. Lipton1dagger

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.

1 Center for Neuroscience and Aging,
2 Program in Cell Adhesion and Extracellular Matrix Biology, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: slipton{at}burnham.org



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Reperfusion-Induced Oxidative/Nitrative Injury to Neurovascular Unit After Focal Cerebral Ischemia.
Y. Gursoy-Ozdemir, A. Can, and T. Dalkara (2004)
Stroke 35, 1449-1453
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Nitric Oxide Inhibits Matrix Metalloproteinase-2 Expression via the Induction of Activating Transcription Factor 3 in Endothelial Cells.
H.-H. Chen and D. L. Wang (2004)
Mol. Pharmacol. 65, 1130-1140
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S-nitrosylation: a potential new paradigm in signal transduction.
A. Martinez-Ruiz and S. Lamas (2004)
Cardiovasc Res 62, 43-52
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S-Nitrosation Regulates the Activation of Endogenous Procaspase-9 in HT-29 Human Colon Carcinoma Cells.
J.-E. Kim and S. R. Tannenbaum (2004)
J. Biol. Chem. 279, 9758-9764
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Matrix Metalloproteinase 1 Interacts with Neuronal Integrins and Stimulates Dephosphorylation of Akt.
K. Conant, C. S. Hillaire, H. Nagase, R. Visse, D. Gary, N. Haughey, C. Anderson, J. Turchan, and A. Nath (2004)
J. Biol. Chem. 279, 8056-8062
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Oxidative Cross-linking of Tryptophan to Glycine Restrains Matrix Metalloproteinase Activity: SPECIFIC STRUCTURAL MOTIFS CONTROL PROTEIN OXIDATION.
X. Fu, J. L. F. Kao, C. Bergt, S. Y. Kassim, N. P. Huq, A. d'Avignon, W. C. Parks, R. P. Mecham, and J. W. Heinecke (2004)
J. Biol. Chem. 279, 6209-6212
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A tautomeric zinc sensor for ratiometric fluorescence imaging: Application to nitric oxide-induced release of intracellular zinc.
C. J. Chang, J. Jaworski, E. M. Nolan, M. Sheng, and S. J. Lippard (2004)
PNAS 101, 1129-1134
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Role of Matrix Metalloproteinases in Delayed Neuronal Damage after Transient Global Cerebral Ischemia.
S.-R. Lee, K. Tsuji, S.-R. Lee, and E. H. Lo (2004)
J. Neurosci. 24, 671-678
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Matrix Metalloproteinase-9 Facilitates Remyelination in Part by Processing the Inhibitory NG2 Proteoglycan.
P. H. Larsen, J. E. Wells, W. B. Stallcup, G. Opdenakker, and V. W. Yong (2003)
J. Neurosci. 23, 11127-11135
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Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis.
A. Bar-Or, R. K. Nuttall, M. Duddy, A. Alter, H. J. Kim, I. Ifergan, C. J. Pennington, P. Bourgoin, D. R. Edwards, and V. W. Yong (2003)
Brain 126, 2738-2749
   Abstract »    Full Text »    PDF »
IL-8/CXCL8 and Growth-Related Oncogene {alpha}/CXCL1 Induce Chondrocyte Hypertrophic Differentiation.
D. Merz, R. Liu, K. Johnson, and R. Terkeltaub (2003)
J. Immunol. 171, 4406-4415
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Nitric Oxide and Cyclic GMP Increase the Expression of Matrix Metalloproteinase-9 in Vascular Smooth Muscle.
M. Marcet-Palacios, K. Graham, C. Cass, A. D. Befus, I. Mayers, and M. W. Radomski (2003)
J. Pharmacol. Exp. Ther. 307, 429-436
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Neurodegeneration in Striatum Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Role of Matrix Metalloproteinase-9 in Early Blood-Brain Barrier Disruption?.
G. W. Kim, Y. Gasche, S. Grzeschik, J.-C. Copin, C. M. Maier, and P. H. Chan (2003)
J. Neurosci. 23, 8733-8742
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Mammalian Osmolytes and S-Nitrosoglutathione Promote {Delta}F508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein Maturation and Function.
M. Howard, H. Fischer, J. Roux, B. C. Santos, S. R. Gullans, P. H. Yancey, and W. J. Welch (2003)
J. Biol. Chem. 278, 35159-35167
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Nitric Oxide and Mechanisms of Redox Signaling.
J. Pfeilschifter, W. Eberhardt, and A. Huwiler (2003)
J. Am. Soc. Nephrol. 14, S237-240
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Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases: Structure, Function, and Biochemistry.
R. Visse and H. Nagase (2003)
Circ. Res. 92, 827-839
   Abstract »    Full Text »    PDF »
Modulation of baroreceptor activity by gene transfer of nitric oxide synthase to carotid sinus adventitia.
S. S. Meyrelles, R. V. Sharma, H. Z. Mao, F. M. Abboud, and M. W. Chapleau (2003)
Am J Physiol Regulatory Integrative Comp Physiol 284, R1190-R1198
   Abstract »    Full Text »    PDF »

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