Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated cancer cell migration

Kevin Zarrabi, Antoine Dufour, Jian Li, Cem Kuscu, Ashleigh Pulkoski-Gross, Jizu Zhi, Youjun Hu, Nicole S. Sampson, Stanley Zucker, Jian Cao

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Matrix metalloproteinases (MMPs) have been shown to be key players in both extracellular matrix remodeling and cell migration during cancer metastasis. MMP-14, a membrane-anchored MMP, in particular, is closely associated with these processes. The hemopexin (PEX) domain of MMP-14 has been proposed as the modulating region involved in the molecular cross-talk that initiates cell migration through homodimerization of MMP-14 as well as heterodimerization with the cell surface adhesion molecule CD44. In this study, minimal regions required for function within the PEX domain were investigated through a series of substitution mutations. Blades I and IV were found to be involved in cell migration. We found that blade IV is necessary for MMP-14 homodimerization and that blade I is required for CD44 MMP-14 heterodimerization. Cross-talk between MMP-14 and CD44 results in phosphorylation of EGF receptor and downstream activation of the MAPK and PI3K signaling pathways involved in cell migration. Based on these mutagenesis analyses, peptides mimicking the essential outermost strand motifs within the PEX domain of MMP-14 were designed. These synthetic peptides inhibit MMP-14-enhanced cell migration in a dose-dependent manner but have no effect on the function of other MMPs. Furthermore, these peptides interfere with cancer metastasis without affecting primary tumor growth. Thus, targeting the MMP-14 hemopexin domain represents a novel approach to inhibit MMP-14-mediated cancer dissemination.

Original languageEnglish (US)
Pages (from-to)33167-33177
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number38
DOIs
StatePublished - Sep 23 2011

Fingerprint

Matrix Metalloproteinase 14
Cell Movement
Cells
Neoplasms
Matrix Metalloproteinases
Hemopexin
Peptides
Neoplasm Metastasis
Mutagenesis
Phosphorylation
Cell Adhesion Molecules
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor Receptor
Extracellular Matrix
Tumors
Substitution reactions
Adhesion
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Zarrabi, K., Dufour, A., Li, J., Kuscu, C., Pulkoski-Gross, A., Zhi, J., ... Cao, J. (2011). Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated cancer cell migration. Journal of Biological Chemistry, 286(38), 33167-33177. https://doi.org/10.1074/jbc.M111.256644

Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated cancer cell migration. / Zarrabi, Kevin; Dufour, Antoine; Li, Jian; Kuscu, Cem; Pulkoski-Gross, Ashleigh; Zhi, Jizu; Hu, Youjun; Sampson, Nicole S.; Zucker, Stanley; Cao, Jian.

In: Journal of Biological Chemistry, Vol. 286, No. 38, 23.09.2011, p. 33167-33177.

Research output: Contribution to journalArticle

Zarrabi, K, Dufour, A, Li, J, Kuscu, C, Pulkoski-Gross, A, Zhi, J, Hu, Y, Sampson, NS, Zucker, S & Cao, J 2011, 'Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated cancer cell migration', Journal of Biological Chemistry, vol. 286, no. 38, pp. 33167-33177. https://doi.org/10.1074/jbc.M111.256644
Zarrabi, Kevin ; Dufour, Antoine ; Li, Jian ; Kuscu, Cem ; Pulkoski-Gross, Ashleigh ; Zhi, Jizu ; Hu, Youjun ; Sampson, Nicole S. ; Zucker, Stanley ; Cao, Jian. / Inhibition of Matrix Metalloproteinase 14 (MMP-14)-mediated cancer cell migration. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 38. pp. 33167-33177.
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