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Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2

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  • Manuel Johanns, de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
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  • Pascale Lemoine, de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
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  • Virginie Janssens, de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
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  • Giuseppina Grieco, de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
  • ,
  • Soren K Moestrup
  • Rikke Nielsen
  • Erik I Christensen
  • Pierre J Courtoy, de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
  • ,
  • Herve Emonard, CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Université de Reims Champagne-Ardenne, 51687, Reims, France.
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  • Etienne Marbaix, de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
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  • Patrick Henriet, de Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium. patrick.henriet@uclouvain.be.

Matrix metalloproteinases (MMPs) are regulated at multiple transcriptional and post-transcriptional levels, among which receptor-mediated endocytic clearance. We previously showed that low-density lipoprotein receptor-related protein-1 (LRP-1) mediates the clearance of a complex between the zymogen form of MMP-2 (proMMP-2) and tissue inhibitor of metalloproteinases, TIMP-2, in HT1080 human fibrosarcoma cells. Here we show that, in BN16 rat yolk sac cells, proMMP-2:TIMP-2 complex is endocytosed through a distinct LRP member, megalin/LRP-2. Addition of receptor-associated protein (RAP), a natural LRP antagonist, caused accumulation of endogenous proMMP-2 and TIMP-2 in conditioned media. Incubation with RAP also inhibited membrane binding and cellular uptake of exogenous iodinated proMMP-2:TIMP-2. Moreover, antibodies against megalin/LRP-2, but not against LRP-1, inhibited binding of proMMP-2:TIMP-2 to BN16 cell surface. BIAcore analysis confirmed direct interaction between the complex and megalin/LRP-2. Conditional renal invalidation of megalin/LRP-2 in mice resulted in accumulation of proMMP-2 and TIMP-2 in their urine, highlighting the physiological relevance of the binding. We conclude that megalin/LRP-2 can efficiently mediate cell-surface binding and endocytosis of proMMP-2:TIMP-2 complex. Therefore megalin/LRP-2 can be considered as a new actor in regulation of MMP-2 activity, an enzyme crucially involved in many pathological processes.

Original languageEnglish
JournalScientific Reports
Volume7
Issue1
Pages (from-to)4328
ISSN2045-2322
DOIs
Publication statusPublished - 28 Jun 2017

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  • Journal Article

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