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

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...

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Autores principales: Johanns, Manuel, Lemoine, Pascale, Janssens, Virginie, Grieco, Giuseppina, Moestrup, Soren K., Nielsen, Rikke, Christensen, Erik I., Courtoy, Pierre J., Emonard, Hervé, Marbaix, Etienne, Henriet, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489529/
https://www.ncbi.nlm.nih.gov/pubmed/28659595
http://dx.doi.org/10.1038/s41598-017-04648-y
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author Johanns, Manuel
Lemoine, Pascale
Janssens, Virginie
Grieco, Giuseppina
Moestrup, Soren K.
Nielsen, Rikke
Christensen, Erik I.
Courtoy, Pierre J.
Emonard, Hervé
Marbaix, Etienne
Henriet, Patrick
author_facet Johanns, Manuel
Lemoine, Pascale
Janssens, Virginie
Grieco, Giuseppina
Moestrup, Soren K.
Nielsen, Rikke
Christensen, Erik I.
Courtoy, Pierre J.
Emonard, Hervé
Marbaix, Etienne
Henriet, Patrick
author_sort Johanns, Manuel
collection PubMed
description 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.
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spelling pubmed-54895292017-07-05 Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2 Johanns, Manuel Lemoine, Pascale Janssens, Virginie Grieco, Giuseppina Moestrup, Soren K. Nielsen, Rikke Christensen, Erik I. Courtoy, Pierre J. Emonard, Hervé Marbaix, Etienne Henriet, Patrick Sci Rep Article 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. Nature Publishing Group UK 2017-06-28 /pmc/articles/PMC5489529/ /pubmed/28659595 http://dx.doi.org/10.1038/s41598-017-04648-y Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Johanns, Manuel
Lemoine, Pascale
Janssens, Virginie
Grieco, Giuseppina
Moestrup, Soren K.
Nielsen, Rikke
Christensen, Erik I.
Courtoy, Pierre J.
Emonard, Hervé
Marbaix, Etienne
Henriet, Patrick
Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2
title Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2
title_full Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2
title_fullStr Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2
title_full_unstemmed Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2
title_short Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2
title_sort cellular uptake of prommp-2:timp-2 complexes by the endocytic receptor megalin/lrp-2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489529/
https://www.ncbi.nlm.nih.gov/pubmed/28659595
http://dx.doi.org/10.1038/s41598-017-04648-y
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