Cellular cholesterol regulates MT1 MMP dependent activation of MMP 2 via MEK-1 in HT1080 fibrosarcoma cells.
Unstimulated human fibrosarcoma cells (HT1080) constitutively secrete matrix metalloproteinase 2 (MMP 2) as a proenzyme requiring proteolytic cleavage by membrane type-1 MMP (MT1 MMP) for activation. Physiological and pharmacological stimuli induce clustering of MT1 MMP/tissue inhibitor of MMP 2 "receptors", promoting binding and activation of MMP 2. We now report that cholesterol depleted HT1080 cells accumulated MT1 MMP on the cell surface and activated MMP 2. A specific inhibitor of mitogen activated protein kinase kinase 1/2 inhibited both MMP 2 activation and extracellular signal-related kinase phosphorylation induced by cholesterol depletion. Our data indicate that the cholesterol content of unstimulated cells is critical for secretion of MMP 2 as an inactive zymogen and control of pericellular proteolysis.
Atkinson
Susan J
SJ
Department of Oncology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, UK.
English
Jane L
JL
Holway
Nicholas
N
Murphy
Gillian
G
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D002784:Cholesterol / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology; D003505:Cyclodextrins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005354:Fibrosarcoma / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D019716:Tissue Inhibitor of Metalloproteinase-2; D002784:Cholesterol; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2