Abstract
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.
Highlights
IntroductionSignificance: Our work reveals a novel mechanism of MT1-matrix metalloproteinase (MMP) regulation during cellular invasion and identifies the MT-LOOP as a novel target region to develop specific inhibitors
MT1-matrix metalloproteinase (MMP) needs to be localized to the leading edge of invading cells
We found that integrin-rich cell adhesion complex can be one of the functional leading edges and that the MT-LOOP region of MT1-MMP is required for the enzyme to localize to this structure
Summary
Significance: Our work reveals a novel mechanism of MT1-MMP regulation during cellular invasion and identifies the MT-LOOP as a novel target region to develop specific inhibitors. 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 1-integrin-rich cell adhesion complexes at the plasma membrane. 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
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