| Role of matrix metalloproteinase-9 dimers in cell migration: design of inhibitory peptides. | |
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MedLine Citation:
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PMID: 20837483 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Non-proteolytic activities of matrix metalloproteinases (MMPs) have recently been shown to impact cell migration, but the precise mechanism remains to be understood. We previously demonstrated that the hemopexin (PEX) domain of MMP-9 is a prerequisite for enhanced cell migration. Using a biochemical approach, we now report that dimerization of MMP-9 through the PEX domain appears necessary for MMP-9-enhanced cell migration. Following a series of substitution mutations within the MMP-9 PEX domain, blade IV was shown to be critical for homodimerization, whereas blade I was required for heterodimerization with CD44. Blade I and IV mutants showed diminished enhancement of cell migration compared with wild type MMP-9-transfected cells. Peptides mimicking motifs in the outermost strands of the first and fourth blades of the MMP-9 PEX domain were designed. These peptides efficiently blocked MMP-9 dimer formation and inhibited motility of COS-1 cells overexpressing MMP-9, HT-1080, and MDA-MB-435 cells. Using a shRNA approach, CD44 was found to be a critical molecule in MMP-9-mediated cell migration. Furthermore, an axis involving a MMP-9-CD44-EGFR signaling pathway in cell migration was identified using antibody array and specific receptor tyrosine kinase inhibitors. In conclusion, we dissected the mechanism of pro-MMP-9-enhanced cell migration and developed structure-based inhibitory peptides targeting MMP-9-mediated cell migration. |
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Authors:
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Antoine Dufour; Stanley Zucker; Nicole S Sampson; Cem Kuscu; Jian Cao |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-09-13 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-08 Completed Date: 2011-02-09 Revised Date: 2013-05-28 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 35944-56 Citation Subset: IM |
Affiliation:
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Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Antigens, CD44 / chemistry, genetics, metabolism Blotting, Western COS Cells Cell Line, Tumor Cell Movement / physiology* Cercopithecus aethiops Enzyme Inhibitors / pharmacology Humans Matrix Metalloproteinase 9 / chemistry*, genetics, metabolism* Models, Molecular Mutation Oligopeptides / chemistry, pharmacology Protein Binding Protein Conformation Protein Multimerization / drug effects, physiology* Protein Structure, Tertiary Quinazolines RNA Interference Receptor, Epidermal Growth Factor / antagonists & inhibitors, metabolism Signal Transduction / drug effects Tissue Inhibitor of Metalloproteinase-1 / chemistry, genetics, metabolism Transfection Tyrphostins / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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5R01CA11355301A1/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD44; 0/Enzyme Inhibitors; 0/Oligopeptides; 0/Quinazolines; 0/Tissue Inhibitor of Metalloproteinase-1; 0/Tyrphostins; 170449-18-0/tyrphostin AG 1478; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.4.24.35/Matrix Metalloproteinase 9 |
| Comments/Corrections | |
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