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

Publikation: Forskning - peer reviewTidsskriftartikel

DOI

  • Manuel Johanns
    Manuel Johannsde Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
  • Pascale Lemoine
    Pascale Lemoinede Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
  • Virginie Janssens
    Virginie Janssensde Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
  • Giuseppina Grieco
    Giuseppina Griecode Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
  • Soren K Moestrup
  • Rikke Nielsen
  • Erik I Christensen
  • Pierre J Courtoy
    Pierre J Courtoyde Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
  • Herve Emonard
    Herve EmonardCNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Université de Reims Champagne-Ardenne, 51687, Reims, France.
  • Etienne Marbaix
    Etienne Marbaixde Duve Institute, Université catholique de Louvain, 1200, Brussels, Belgium.
  • Patrick Henriet
    Patrick Henrietde 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.

OriginalsprogEngelsk
TidsskriftScientific reports
Vol/bind7
Tidsskriftsnummer1
Sider (fra-til)4328
ISSN2045-2322
DOI
StatusUdgivet - 28 jun. 2017

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