The protease MT1-MMP drives a combinatorial proteolytic program in activated endothelial cells

Area of Science:

• Cell Biology
• Biochemistry
• Molecular Biology

Background:

• Pericellular proteolysis links protease activity to biological responses, but mechanisms remain unclear.
• Understanding protease function in inflammation is crucial for studying capillary sprouting and angiogenesis.

Purpose of the Study:

• Identify the substrates of matrix metalloproteinase 1 (MT1-MMP) in endothelial tip cells activated by inflammatory stimuli.
• Explore the role of MT1-MMP in pericellular proteolysis during inflammation and its impact on endothelial cell functions.

Main Methods:

• Quantitative proteomics was used on endothelial cells (ECs) from wild-type and MT1-MMP-null mice.
• Cells were stimulated with Tumor Necrosis Factor-alpha (TNF-α) to induce inflammatory responses.
• Bioinformatics analysis was employed to identify MT1-MMP substrates and proteolytic pathways.

Main Results:

• A combinatorial MT1-MMP proteolytic program was identified, where combined substrate processing dictates EC biological decisions.
• Key EC functions influenced include chemotaxis, cell motility, adhesion, and vasculature development.
• MT1-MMP-deficient ECs showed inefficient processing of substrates like TSP1, CYR61, NID1, and SEM3C, validating the findings.

Conclusions:

• MT1-MMP drives angiogenesis through a novel combinatorial proteolysis mechanism in endothelial cells.
• This proteolysis strategy regulates inflammatory responses and vascular development.
• The concept of MT1-MMP-driven combinatorial proteolysis may extend to other cellular contexts beyond angiogenesis.