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PubMed · 11331272

Functional interplay between type I collagen and cell surface matrix metalloproteinase activity.

S M Ellerbroek·Y I Wu·C M Overall·M S Stack
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Abstract

Type I collagen stimulation of pro-matrix metalloproteinase (pro-MMP)-2 activation by ovarian cancer cells involves beta(1) integrin receptor clustering; however, the specific cellular and biochemical events that accompany MMP processing are not well characterized. Collagenolysis is not required for stimulation of pro-MMP-2 activation, and denatured collagen does not elicit an MMP-2 activation response. Similarly, DOV13 cells bind to intact collagen utilizing both alpha(2)beta(1) and alpha(3)beta(1) integrins but interact poorly with collagenase-treated or thermally denatured collagen. Antibody-induced clustering of alpha(3)beta(1) strongly promotes activation of pro-MMP-2, whereas alpha(2)beta(1) integrin clustering has only marginal effects. Membrane-type 1 (MT1)-MMP is present on the DOV13 cell surface as both an active 55-kDa TIMP-2-binding species and a stable catalytically inactive 43-kDa form. Integrin clustering stimulates cell surface expression of MT1-MMP and co-localization of the proteinase to aggregated integrin complexes. Furthermore, cell surface proteolysis of the 55-kDa MT1-MMP species occurs in the absence of active MMP-2, suggesting MT1-MMP autolysis. Cellular invasion of type I collagen matrices requires collagenase activity, is blocked by tissue inhibitor of metalloproteinases-2 (TIMP-2) and collagenase-resistant collagen, is unaffected by TIMP-1, and is accompanied by pro-MMP-2 activation. Together, these data indicate that integrin stimulation of MT1-MMP activity is a rate-limiting step for type I collagen invasion and provide a mechanism by which this activity can be down-regulated following collagen clearance.

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Cell AdhesionCell LineCollagenEnzyme ActivationEnzyme PrecursorsFemaleGelatinasesHumansImmunohistochemistryIntegrinsMatrix Metalloproteinase 2Matrix MetalloproteinasesMetalloendopeptidasesMolecular WeightOvarian NeoplasmsStructure-Activity RelationshipSurface PropertiesTissue Inhibitor of Metalloproteinase-2Tumor Cells, CulturedJournal ArticleResearch Support, U.S. Gov't, Non-P.H.S.Research Support, U.S. Gov't, P.H.S.

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S M Ellerbroek, Y I Wu, C M Overall, M S Stack. 2001-04-30. Functional interplay between type I collagen and cell surface matrix metalloproteinase activity.. https://doi.org/10.1074/jbc.m005631200

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