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

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2017-01-01 | GSE85597 | GEO

Expression array of early postnatal Mt1-mmp-targeted mammary glands

Project description:Mammary gland branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases, MT1-MMP and MT2-MMP, that drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remains undefined. A mammary gland branching program that occurs during the first 10 days of early postnatal development was used to characterize the impact of global Mt1-mmp or Mt2-mmp targeting on mammary gland morphogenesis. Transcriptome profiling of ductal networks and associated stroma was used to investigate the functional roles of MT1-MMP in the early postnatal mammary gland in an unbiased fashion.

2016-10-05 | GSE77677 | GEO

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

Project description:Mammary gland branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases, MT1-MMP and MT2-MMP, that drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remains undefined. A mammary gland branching program that occurs during the first 10 days of early postnatal development was used to characterize the impact of global Mt1-mmp or Mt2-mmp targeting on mammary gland morphogenesis. Transcriptome profiling of ductal networks and associated stroma was used to investigate the functional roles of MT2-MMP in the early postnatal mammary gland in an unbiased fashion.

2016-10-05 | GSE77678 | GEO

MT1-MMP (MMP14)-dependent gene expression in APOE-null vascular smooth muscle cells (VSMCs)

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2017-08-01 | GSE100661 | GEO

Degradomic identification of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14) as an ADAMTS9 and ADAMTS20 substrate

Project description:ADAMTS9 and ADAMTS20 are homologous secreted proteases implicated in ECM proteolysis and ciliogenesis, but few relevant substrates of these proteases are currently known. Quantitative N-terminomics comparison of RPE-1 cells lacking ADAMTS9 with parental RPE-1 cells identified transmembrane protease MT1-MMP (MMP14) as a novel ADAMTS9 substrate. The resulting enhanced cell-surface MT1-MMP activity in the gene-edited cells contributes to their adhesion defect, but not lack of cilia. A key physiological function of ADAMTS9/20 may be to dampen cell-surface MT1-MMP activity.

2023-07-20 | PXD036612 | Pride

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

Project description:In order to investigate the impact of MMP-14 (MT1-MMP) on the transcriptomes of a human breast adenocarcinoma cell line, we performed a microarray analysis from RNAs isolated from MCF-7 cells expressing either an empty vector (VEC) or human MMP-14 cDNA (MT1) in monolayer growth conditions.

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Expression array of Mt1-mmp+/+ and Mt1-mmp-/- mouse macrophages in response to LPS or IL-4

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Comparison of gene expression in mouse placentas with different combination of MT1-MMP and MT2-MMP alleles

Project description:MT1-MMP and MT2-MMP double deficiency in mice leads to development of a placental defect resulting in embryonic death after E10.5. The protein substrate for these two proteases in placenta is unknown, which poses an obstacle in uncovering of molecular mechanism behind the observed placental defect. In search for a potential substrate for these two proteases in placenta we have employed whole genome microarray expression profiling as a discovery platform to identify genes, expression of which might be affected by double MMP deficiency. Fetal parts of mouse placentas were isolated from E10.5 placentas of different genotypes for MT1- and MT2-MMP.

2010-03-09 | E-GEOD-18604 | biostudies-arrayexpress

Molecular Signature of MT1-MMP: Transactivation of the Downstream Universal Gene in Cancer

Project description:Genome-wide expression profiling of MT1-MMP–overexpressing versus MT1-MMP–silenced cancer cells and a further data mining analysis of the preexisting expression database of 190 human tumors of 14 cancer types led us to identify 11 genes, the expression of which correlated firmly and universally with that of MT1-MMP (P < 0.00001).

2008-06-11 | GSE11668 | GEO

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