Low Density Lipoprotein Receptor-related Protein Mediates Endocytic Clearance of Pro-MMP-2·TIMP-2 Complex through a Thrombospondin-independent Mechanism

The low density lipoprotein receptor-related protein (LRP) mediates the endocytic clearance of various proteinases and proteinase·inhibitor complexes, including thrombospondin (TSP)-dependent endocytosis of matrix metalloproteinase (MMP)-2 (or gelatinase A), a key effector of extracellular matrix re...

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Veröffentlicht in:The Journal of biological chemistry 2004-12, Vol.279 (52), p.54944-54951
Hauptverfasser: Emonard, Hervé, Bellon, Georges, Troeberg, Linda, Berton, Alix, Robinet, Arnaud, Henriet, Patrick, Marbaix, Etienne, Kirkegaard, Kirstine, Patthy, László, Eeckhout, Yves, Nagase, Hideaki, Hornebeck, William, Courtoy, Pierre J.
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Sprache:eng
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Zusammenfassung:The low density lipoprotein receptor-related protein (LRP) mediates the endocytic clearance of various proteinases and proteinase·inhibitor complexes, including thrombospondin (TSP)-dependent endocytosis of matrix metalloproteinase (MMP)-2 (or gelatinase A), a key effector of extracellular matrix remodeling and cancer progression. However, the zymogen of MMP-2 (pro-MMP-2) mostly occurs in tissues as a complex with the tissue inhibitor of MMPs (TIMP-2). Here we show that clearance of the pro-MMP-2·TIMP-2 complex is also mediated by LRP, because addition of receptor-associated protein (RAP), a natural LRP ligand antagonist, inhibited endocytosis and lysosomal degradation of 125I-pro-MMP-2·TIMP-2. Both TIMP-2 and the pro-MMP-2 collagen-binding domain independently competed for endocytosis of 125I-pro-MMP-2·TIMP-2 complex. Surface plasmon resonance studies indicated that pro-MMP-2, TIMP-2, and pro-MMP-2·TIMP-2 directly interact with LRP in the absence of TSP. LRP-mediated endocytic clearance of 125I-pro-MMP-2 was inhibited by anti-TSP antibodies and accelerated upon complexing with TSP-1, but these treatments had no effect on 125I-pro-MMP-2·TIMP-2 uptake. This implies that mechanisms of clearance by LRP of pro-MMP-2 and pro-MMP-2·TIMP-2 complex are different. Interestingly, RAP did not inhibit binding of 125I-pro-MMP-2·TIMP-2 to the cell surface. We conclude that clearance of pro-MMP-2·TIMP-2 complex is a TSP-independent two-step process, involving (i) initial binding to the cell membrane in a RAP-insensitive manner and (ii) subsequent LRP-dependent (RAP-sensitive) internalization and degradation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M406792200