ECM regulates MT1-MMP localization with beta1 or alphavbeta3 integrins at distinct cell compartments modulating its internalization and activity on human endothelial cells.
Regulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) by different extracellular matrices (ECMs) on human endothelial cells (ECs) has been investigated. First, MT1-MMP is found at the intercellular contacts of confluent ECs grown on beta1 integrin-dependent matrix such as type 1 collagen (COL I), fibronectin (FN), or fibrinogen (FG), but not on gelatin (GEL) or vitronectin (VN). The novel localization of MT1-MMP at cell-cell contacts is assessed by confocal videomicroscopy of MT1-MMP-GFP-transfected ECs. Moreover, MT1-MMP colocalizes with beta1 integrins at the intercellular contacts, whereas it is preferentially found with alphavbeta3 integrin at motility-associated structures on migrating ECs. In addition, clustered integrins recruit MT1-MMP and neutralizing anti-beta1 or anti-alphav integrin mAb displace MT1-MMP from its specific sites, pointing to a biochemical association that is finally demonstrated by coimmunoprecipitation assays. On the other hand, COL I, FN, or FG up-regulate cell surface MT1-MMP on confluent ECs by an impairment of its internalization, whereas expression and internalization are not modified on GEL or VN. In addition, MT1-MMP activity is diminished in confluent ECs on COL I, FN, or FG. Finally, MT1-MMP participates and cooperates with beta1 and alphavbeta3 integrins in the migration of ECs on different ECM. These data show a novel mechanism by which ECM regulates MT1-MMP association with beta1 or alphavbeta3 integrins at distinct cellular compartments, thus modulating its internalization, activity, and function on human ECs.
Gálvez
Beatriz G
BG
Departamento de Inmunología, Hospital de la Princesa, C/Diego de León 62, 28006 Madrid, Spain.
Matías-Román
Salomón
S
Yáñez-Mó
María
M
Sánchez-Madrid
Francisco
F
Arroyo
Alicia G
AG
D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D018715:Microscopy, Video; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D039302:Integrin alphaVbeta3; D019012:Integrin beta1; D011993:Recombinant Fusion Proteins; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases