Role of matrix metalloproteinase-9 dimers in cell migration

Design of inhibitory peptides

Antoine Dufour, Stanley Zucker, Nicole S. Sampson, Cem Kuscu, Jian Cao

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)35944-35956
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number46
DOIs
StatePublished - Nov 12 2010

Fingerprint

Matrix Metalloproteinase 9
Dimers
Cell Movement
Peptides
Hemopexin
Dimerization
COS Cells
Receptor Protein-Tyrosine Kinases
Matrix Metalloproteinases
Small Interfering RNA
Substitution reactions
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Role of matrix metalloproteinase-9 dimers in cell migration : Design of inhibitory peptides. / Dufour, Antoine; Zucker, Stanley; Sampson, Nicole S.; Kuscu, Cem; Cao, Jian.

In: Journal of Biological Chemistry, Vol. 285, No. 46, 12.11.2010, p. 35944-35956.

Research output: Contribution to journalArticle

Dufour, Antoine ; Zucker, Stanley ; Sampson, Nicole S. ; Kuscu, Cem ; Cao, Jian. / Role of matrix metalloproteinase-9 dimers in cell migration : Design of inhibitory peptides. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 46. pp. 35944-35956.
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