Functional relationship between matrix metalloproteinase-11 and matrix metalloproteinase-14.

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Biology

Background:

• Matrix metalloproteinase-11 (MMP-11) is crucial for tissue remodeling and its activity requires tight regulation.
• Tissue inhibitors of metalloproteinases (TIMPs) reversibly inhibit MMP-11, but irreversible inactivation mechanisms may also exist.

Purpose of the Study:

• To investigate the potential role of MMP-14 in the regulation of MMP-11 activity.
• To explore MMP-14 as a potential MMP-11 inactivator through proteolytic cleavage.

Main Methods:

• Utilized native and recombinant MMP-11 and MMP-14 proteins from human and mouse sources.
• Performed in vitro cleavage assays to identify MMP-14 substrate sites on MMP-11.
• Assessed the functional impact of MMP-14 cleavage on MMP-11 enzymatic activity.

Main Results:

• MMP-11 was identified as a substrate of MMP-14, with cleavage occurring at two novel sites within the catalytic domain.
• Active MMP-14 significantly reduced MMP-11 enzymatic activity, while inactive MMP-14 had no effect.
• This MMP-dependent inactivation mechanism is conserved between human and mouse.

Conclusions:

• MMP-14 irreversibly inactivates MMP-11 through proteolytic cleavage, complementing the canonical TIMP-dependent inhibition.
• This finding highlights the significance of tumor-stroma interactions, with MMP-14 from cancer cells regulating MMP-11 from stromal cells.
• MMP-14's dual role in activating some MMPs while inactivating MMP-11 suggests complex regulation within the MMP cascade and pericellular environment.