Document Detail

Role of matrix metalloproteinase-9 dimers in cell migration: design of inhibitory peptides.
MedLine Citation:
PMID:  20837483     Owner:  NLM     Status:  MEDLINE    
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.
Antoine Dufour; Stanley Zucker; Nicole S Sampson; Cem Kuscu; Jian Cao
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Publication Detail:
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:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-08     Completed Date:  2011-02-09     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  35944-56     Citation Subset:  IM    
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MeSH Terms
Amino Acid Sequence
Antigens, CD44 / chemistry,  genetics,  metabolism
Blotting, Western
COS Cells
Cell Line, Tumor
Cell Movement / physiology*
Cercopithecus aethiops
Enzyme Inhibitors / pharmacology
Matrix Metalloproteinase 9 / chemistry*,  genetics,  metabolism*
Models, Molecular
Oligopeptides / chemistry,  pharmacology
Protein Binding
Protein Conformation
Protein Multimerization / drug effects,  physiology*
Protein Structure, Tertiary
RNA Interference
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  metabolism
Signal Transduction / drug effects
Tissue Inhibitor of Metalloproteinase-1 / chemistry,  genetics,  metabolism
Tyrphostins / pharmacology
Grant Support
5R01CA11355301A1/CA/NCI NIH HHS; R01 CA113553/CA/NCI NIH HHS
Reg. No./Substance:
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, Epidermal Growth Factor; EC Metalloproteinase 9

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