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Matrilysin (MMP-7) catalytic activity regulates β-catenin localization and signaling activation in lung epithelial
1Department of Pediatrics and Center for Lung Biology, University of Washington , Seattle, Washington , USA.
Abstract:
Matrix metalloproteinase-7 (matrilysin, MMP-7) expression is increased in epithelium by bacterial infection, inflammation, fibrosis, and in a myriad of carcinomas. It functions to degrade extracellular matrix and other pericellular substrates including the adherens junction protein E-cadherin to promote wound healing and tissue remodeling. β-catenin functions as both a structural component of adherens junctions and as an intracellular signaling molecule. To assess if matrilysin-mediated disassembly of adherens junctions regulates β-catenin function, we assessed effects of matrilysin catalytic activity on β-catenin localization and signaling activity in A549 cells and in bleomycin-induced lung injury in mice. We determined that matrilysin activity releases β-catenin from the cell membrane after which it is degraded in the cytosol. However, in the presence of a β-catenin stabilizing Wnt signal, β-catenin accumulated in the cytosol and activated a β-catenin luciferase promoter. Furthermore, β-catenin nuclear translocation and activation was impaired in matrilysin-null mice when compared to wild-type mice after bleomycin-induced lung injury. These results show identify matrilysin as a regulator of β-catenin function in injured lung epithelium and may link extracellular proteolytic activity to cell junction disassembly and intracellular signaling.
Insights
Matrix metalloproteinase-7 (MMP-7) regulates β-catenin by releasing it from cell junctions, impacting its signaling. This finding links extracellular proteolysis to intracellular signaling in injured lung epithelium.
Area of Science:
- Biochemistry
- Cell Biology
- Pulmonary Medicine
Background:
- Matrix metalloproteinase-7 (MMP-7), also known as matrilysin, is upregulated in epithelial tissues during bacterial infection, inflammation, fibrosis, and various carcinomas.
- MMP-7 degrades extracellular matrix and E-cadherin, facilitating wound healing and tissue remodeling.
- β-catenin is crucial for adherens junctions and intracellular signaling.
Purpose of the Study:
- To investigate if MMP-7-mediated adherens junction disassembly influences β-catenin localization and signaling.
- To assess the impact of MMP-7 catalytic activity on β-catenin in A549 cells and a mouse model of lung injury.
Main Methods:
- Assessed β-catenin localization and signaling activity in A549 cells treated with MMP-7.
- Utilized a bleomycin-induced lung injury model in wild-type and matrilysin-null mice.
- Measured β-catenin release, degradation, nuclear translocation, and promoter activation.
Main Results:
- MMP-7 activity releases cell membrane-bound β-catenin, leading to its cytosolic degradation.
- In the presence of Wnt signaling, MMP-7 activity causes β-catenin accumulation and activation of a β-catenin luciferase promoter.
- Matrilysin-null mice exhibited impaired β-catenin nuclear translocation and activation following bleomycin-induced lung injury compared to wild-type mice.
Conclusions:
- MMP-7 acts as a regulator of β-catenin function in injured lung epithelium.
- Extracellular proteolytic activity, specifically MMP-7, can influence cell junction integrity and intracellular signaling pathways.
- These findings establish a link between MMP-7, cell junction disassembly, and β-catenin-mediated signaling in the context of lung injury.
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