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Inhibition of ß1 integrin induces its association with MT1-MMP and decreases MT1- MMP internalization and cellular invasiveness

ABSTRACT: Integrin signaling plays a fundamental role in the establishment of focal adhesions and the subsequent formation of invadopodia in malignant cancer cells. Invadopodia facilitate localized adhesion and degradation of the extracellular matrix (ECM), which promote tumour cell invasion and metastasis. Degradation of ECM components is often driven by membrane type-1 matrix metalloproteinase (MT1-MMP), and we have recently shown that regulation of enzyme internalization is dependent on signaling downstream of β1 integrin. Phosphorylation of the cytoplasmic tail of MT1-MMP is required for its internalization and delivery to Rab5-marked early endosomes, where it is then able to be recycled to new sites of invadopodia formation and promote invasion. Here we found that inhibition of β1 integrin, using the antibody AIIB2, inhibited the internalization and recycling of MT1-MMP that is necessary to support long-term cellular invasion. MT1-MMP and β1 integrin were sequestered at the cell surface when β1-integrin was inhibited, and their association under these conditions was detected using immunoprecipitation and mass spectrometry analysis. Sequestration of β1 integrin and MT1-MMP at the cell surface resulted in the formation of large invadopodia and local ECM degradation; however, the impaired internalization and recycling of MT1-MMP and β1 integrin ultimately led to a loss of invasive behaviour.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Jennifer Geddes-McAlister

LAB HEAD: Jennifer Geddes-McAlister

PROVIDER: PXD024000 | Pride | 2022-12-22

REPOSITORIES: Pride

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	JGM-Lilianne-A1.raw	Raw
	JGM-Lilianne-A2.raw	Raw
	JGM-Lilianne-A3.raw	Raw
	JGM-Lilianne-U1.raw	Raw
	JGM-Lilianne-U2.raw	Raw

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Extracellular Matrix Proteolysis by MT1-MMP is Associated with Influenza-Related Mortality

Project description:The balance between protecting tissue integrity and efficient immune response is critical for host survival. Here we investigate the role of extracellular matrix (ECM) proteolysis in achieving this balance in the lung during influenza virus infection using a combined genomic and proteomic approach. We followed the transcriptional dynamics and ECM- related responses in a mouse model of influenza virus infection, integrated with whole tissue imaging and functional assays. Our study identifies MT1-MMP as a prominent host-ECM-remodeling collagenase in influenza virus infection. We show that selective inhibition of MT1-MMP-driven ECM proteolysis protects the tissue from infection-related structural and compositional damage. Inhibition of MT1-MMP did not significantly alter the immune response or cytokine expression, indicating its dominant role in ECM remodeling. We demonstrate that the available treatment for influenza virus (Tamiflu/ Oseltamivir) does not prevent lung ECM damage and is less effective than anti-MT1-MMP treatment in influenza virus and Streptococcus pneumoniae coinfection paradigms. Importantly, combination therapy of Tamiflu with anti-MT1-MMP shows a strong synergistic effect and results in complete recovery in mice. This study highlights the importance of tissue tolerance agents for surviving infectious diseases, and the potential of such host-pathogen therapy combination for respiratory infections.

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Expression array of early postnatal Mt2-mmp-targeted mammary glands

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Genome-wide analysis of MCF-7 cells expressing or not MMP-14 (MT1-MMP) growing in monolayer cell culture conditions

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