Intracellular processing and activation of membrane type 1 matrix metalloprotease depends on its partitioning into lipid domains.
The integral membrane type 1 matrix metalloprotease (MT1-MMP) is a pivotal protease in a number of physiological and pathological processes and confers both non-tumorigenic and tumorigenic cell lines with a specific growth advantage in a three-dimensional matrix. Here we show that, in a melanoma cell line, the majority (80%) of MT1-MMP is sorted to detergent-resistant membrane fractions; however, it is only the detergent-soluble fraction (20%) of MT1-MMP that undergoes intracellular processing to the mature form. Also, this processed MT1-MMP is the sole form responsible for ECM degradation in vitro. Finally, furin-dependent processing of MT1-MMP is shown to occur intracellularly after exit from the Golgi apparatus and prior to its arrival at the plasma membrane. It is thus proposed that the association of MT1-MMP with different membrane subdomains might be crucial in the control of its different activities: for instance in cell migration and invasion and other less defined ones such as MT1-MMP-dependent signaling pathways.
Mazzone
Marco
M
Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, S. Maria Imbaro, 66030, Chieti, Italy.
Baldassarre
Massimiliano
M
Beznoussenko
Galina
G
Giacchetti
Giada
G
Cao
Jian
J
Zucker
Stanley
S
Luini
Alberto
A
Buccione
Roberto
R
D019921:Biotinylation; D002451:Cell Compartmentation; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D045683:Furin / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053504:Matrix Metalloproteinases, Membrane-Associated; D008545:Melanoma / Q000201:enzymology / Q000473:pathology; D008666:Metalloendopeptidases / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport
D049452:Green Fluorescent Proteins; D045683:Furin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases