MT-LOOP-dependent localization of membrane type I matrix metalloproteinase (MT1-MMP) to the cell adhesion complexes promotes cancer cell invasion.

Journal article

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.

Authors: Woskowicz, A; Weaver, SA; Shitomi, Y; Ito, N; Itoh, Y

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 288
• Issue: 49
• Pages: 35126-35137
• Publication date: 2013-12-01
• DOI: 10.1074/jbc.m113.496067
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Cercopithecus aethiops; Protein Structure, Tertiary; Sequence Deletion; Models, Biological; Cell Adhesion; COS Cells; Gelatinases; Humans; Extracellular Matrix; Amino Acid Sequence; Recombinant Proteins; Animals; Neoplasm Invasiveness; Enzyme Precursors; Hela Cells; Matrix Metalloproteinase 14