Inhibition of matrix metalloproteinase 14 (MMP-14)-mediated cancer cell migration.

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.

• Authors: Kevin Zarrabi, Antoine Dufour, Jian Li, Cem Kuscu, Ashleigh Pulkoski-Gross, Jizu Zhi, Youjun Hu, Nicole S Sampson, Stanley Zucker, Jian Cao
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 38 Pg. 33167-77 (Sep 23 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21795678 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hyaluronan Receptors
• Matrix Metalloproteinase Inhibitors
• Peptides
• ErbB Receptors
• Matrix Metalloproteinase 2
• MMP14 protein, human
• Matrix Metalloproteinase 14

Topics

• Amino Acid Motifs
• Amino Acid Sequence
• Animals
• Breast Neoplasms (blood supply, enzymology, mortality, pathology)
• COS Cells
• Cell Line, Tumor
• Cell Movement (drug effects)
• Chickens
• Chlorocebus aethiops
• Enzyme Activation (drug effects)
• ErbB Receptors (metabolism)
• Female
• Humans
• Hyaluronan Receptors (metabolism)
• Matrix Metalloproteinase 14 (chemistry, metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase Inhibitors
• Mice
• Molecular Sequence Data
• Neovascularization, Pathologic (enzymology)
• Peptides (chemistry, pharmacology)
• Protein Structure, Tertiary
• Signal Transduction (drug effects)
• Survival Rate