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Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases
1Department of Internal Medicine and the University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Abstract:
Membrane type-1 matrix metalloproteinase (MT1-MMP) is the prototypical member of a subgroup of membrane-anchored proteinases that belong to the matrix metalloproteinase family. Although synthesized as a zymogen, MT1-MMP plays an essential role in extracellular matrix remodeling after an undefined process that unmasks its catalytic domain. We now report the existence of a proprotein convertase-MT1-MMP axis that regulates the processing and functional activity of the metalloproteinase. Two sets of basic motifs in the propeptide region of MT1-MMP are identified that potentially can be recognized by the proprotein convertase family of subtilisin-like proteases. Processing of proMT1-MMP as well as the expression of its proteolytic activity were blocked by mutating these recognition motifs or by inhibiting the proprotein convertases furin and PC6 with the serpin-based inhibitor alpha(1) antitrypsin Portland. Furthermore, both furin-dependent and furin-independent MT1-MMP processing pathways are identified that require tethering of the metalloproteinase to the cell surface. These findings demonstrate the existence of a proprotein convertase-MT1-MMP axis that can regulate extracellular matrix remodeling.
Insights
A newly discovered proprotein convertase-MT1-MMP axis regulates matrix metalloproteinase-1 (MT1-MMP) processing and activity. This axis is crucial for extracellular matrix remodeling, involving specific motifs and cell-surface tethering.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Membrane type-1 matrix metalloproteinase (MT1-MMP) is key for extracellular matrix remodeling.
- MT1-MMP is synthesized as an inactive zymogen, requiring activation through an undefined process.
Purpose of the Study:
- To elucidate the regulatory mechanisms governing MT1-MMP processing and activation.
- To identify the role of proprotein convertases in MT1-MMP functional activity.
Main Methods:
- Mutational analysis of MT1-MMP propeptide recognition motifs.
- Inhibition of proprotein convertases (furin and PC6) using alpha(1) antitrypsin Portland.
- Investigation of MT1-MMP processing pathways dependent on cell-surface tethering.
Main Results:
- Two basic motif sets in the MT1-MMP propeptide were identified as potential proprotein convertase recognition sites.
- Mutating these motifs or inhibiting furin/PC6 blocked MT1-MMP processing and proteolytic activity.
- Both furin-dependent and -independent MT1-MMP processing pathways were observed, contingent on cell-surface tethering.
Conclusions:
- A proprotein convertase-MT1-MMP axis regulates MT1-MMP processing and activity.
- This axis plays a significant role in controlling extracellular matrix remodeling.