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Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases implicated in tumor invasion and metastasis, must undergo zymogen activation prior to expressing any proteolytic activity. Although the cysteine-switch model predicts the well-established autoactivation process, approximately 40% of the known MMPs possess a conserved RXKR motif between their pro- and catalytic domains and, thus, could be activated directly by members of the proprotein convertase family. To further understand this process, we analyzed the activation of proMT3-MMP as a model system. We demonstrated that the conversion of MT3-MMP zymogen into active form is dependent on both the furin-type convertase activity and the R(116)RKR motif. Consistently, MT3-MMP was colocalized with furin in the trans-Golgi network by confocal microscopy. However, neither furin activity nor its recognition site in MT3-MMP is required for the observed colocalization. In fact, the colocalization pattern remains intact, even in the presence of brefeldin A, an agent known to block endoplasmic reticulum to Golgi trafficking. Yet, brefeldin A completely blocked the activation of MT3-MMP. A23187, a calcium ionophore known to block furin maturation, also blocked proMT3-MMP activation but had minimal effect on the colocalization between MT3-MMP and furin. Thus, furin processes MT3-MMP zymogen in the trans-Golgi network, where they colocalize independently of their apparent enzyme-substrate relationship.

Type

Journal article

Journal

Cancer research

Publication Date

02/2002

Volume

62

Pages

675 - 681

Addresses

Department of Pharmacology, University of Minnesota, 321 Church Street S.E., 6-120 Jackson Hall, Minneapolis, MN 55455, USA.

Keywords

Kidney, Cell Line, COS Cells, Golgi Apparatus, Animals, Dogs, Enzyme Precursors, Metalloendopeptidases, Furin, Subtilisins, Protein Processing, Post-Translational, Enzyme Activation, Amino Acid Sequence, Sequence Homology, Amino Acid, Molecular Sequence Data, Matrix Metalloproteinases, Membrane-Associated