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Localization of membrane type I matrix metalloproteinase (MT1-MMP) to the leading edge is thought to be a crucial step during cancer cell invasion. However, its mechanisms and functional impact on cellular invasion have not been clearly defined. In this report, we have identified the MT-LOOP, a loop region in the catalytic domain of MT1-MMP ((163)PYAYIREG(170)), as an essential region for MT1-MMP to promote cellular invasion. Deletion of the MT-LOOP effectively inhibited functions of MT1-MMP on the cell surface, including proMMP-2 activation, degradation of gelatin and collagen films, and cellular invasion into a collagen matrix. This is not due to loss of the catalytic function of MT1-MMP but due to inefficient localization of the enzyme to β1-integrin-rich cell adhesion complexes at the plasma membrane. We also found that an antibody that specifically recognizes the MT-LOOP region of MT1-MMP (LOOPAb) inhibited MT1-MMP functions, fully mimicking the phenotype of the MT-LOOP deletion mutant. We therefore propose that the MT-LOOP region is an interface for molecular interactions that mediate enzyme localization to cell adhesion complexes and regulate MT1-MMP functions. Our findings have revealed a novel mechanism regulating MT1-MMP during cellular invasion and have identified the MT-LOOP as a potential exosite target region to develop selective MT1-MMP inhibitors.

Original publication

DOI

10.1074/jbc.M113.496067

Type

Journal

J Biol Chem

Publication Date

06/12/2013

Volume

288

Pages

35126 - 35137

Keywords

Cell Invasion, Cell Surface Enzymes, Focal Adhesion, Integrin, Invasion, MT-LOOP, MT1-MMP, Matrix Metalloproteinase (MMP), Amino Acid Sequence, Animals, COS Cells, Cell Adhesion, Cercopithecus aethiops, Enzyme Precursors, Extracellular Matrix, Gelatinases, HeLa Cells, Humans, Matrix Metalloproteinase 14, Models, Biological, Neoplasm Invasiveness, Protein Structure, Tertiary, Recombinant Proteins, Sequence Deletion