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Proteolytic activation of the precursor of membrane type 1 matrix metalloproteinase by human plasmin. A possible cell
1Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Japan.
Abstract:
Membrane type 1 matrix metalloproteinase (MT1-MMP) was suggested to play a critical role in the regulation of tissue invasion by normal and neoplastic cells by directly mediating the activation of pro-gelatinase A. Recently, the proteolytic activation of a pro-MT1-MMP by an intracellular proprotein convertase, furin, was reported. In this study, we found that plasmin efficiently activates the pro-MT1-MMP by cleaving immediately downstream of Arg108 and Arg111 in the multi-basic motif between its pro- and catalytic domains that participates in the activation of pro-gelatinase A. Our present data suggest that pro-MT1-MMP transported to the plasma membrane is activated by plasmin extracellularly and thus it may play an important role in the matrix degradation process.
Insights
Plasmin activates pro-matrix metalloproteinase 1 (MT1-MMP) extracellularly by cleaving specific sites. This extracellular activation suggests a key role for plasmin in MT1-MMP
Area of Science:
- Biochemistry
- Cell Biology
- Extracellular Matrix Biology
Background:
- Membrane type 1 matrix metalloproteinase (MT1-MMP) regulates cell invasion and matrix degradation.
- MT1-MMP activates pro-gelatinase A, contributing to tissue remodeling.
- Intracellular activation of pro-MT1-MMP by furin has been previously reported.
Purpose of the Study:
- To investigate the role of plasmin in the activation of pro-MT1-MMP.
- To identify the specific cleavage sites involved in plasmin-mediated activation.
- To determine the location of pro-MT1-MMP activation.
Main Methods:
- In vitro cleavage assays using purified pro-MT1-MMP and plasmin.
- Mass spectrometry to identify cleavage sites.
- Analysis of pro-MT1-MMP processing and localization.
Main Results:
- Plasmin efficiently activates pro-MT1-MMP.
- Cleavage occurs downstream of Arg108 and Arg111 within the multi-basic motif.
- Data suggest extracellular activation of pro-MT1-MMP at the plasma membrane.
Conclusions:
- Plasmin is an extracellular activator of pro-MT1-MMP.
- Extracellular activation by plasmin is crucial for MT1-MMP's role in matrix degradation.
- This finding highlights a novel pathway in extracellular matrix remodeling and cell invasion.