Low density lipoprotein receptor-related protein mediates endocytic clearance of pro-MMP-2-TIMP-2 complex through a thrombospondin-independent mechanism

Hervé Emonard, Georges Bellon, Linda Troeberg, Alix Berton, Arnaud Robinet, Patrick Henriet, Etienne Marbaix, Kirstine Kirkegaard, László Patthy, Yves Eeckhout, Hideaki Nagase, William Hornebeck, Pierre J. Courtoy

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Abstract

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 MHPs (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, andpro-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 (KAP-sensitive) internalization and degradation.

Original languageEnglish
Pages (from-to)54944-54951
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number52
DOIs
Publication statusPublished - Dec 24 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Emonard, H., Bellon, G., Troeberg, L., Berton, A., Robinet, A., Henriet, P., Marbaix, E., Kirkegaard, K., Patthy, L., Eeckhout, Y., Nagase, H., Hornebeck, W., & Courtoy, P. J. (2004). Low density lipoprotein receptor-related protein mediates endocytic clearance of pro-MMP-2-TIMP-2 complex through a thrombospondin-independent mechanism. Journal of Biological Chemistry, 279(52), 54944-54951. https://doi.org/10.1074/jbc.M406792200