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

Abstract 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...

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Autores principales:	Manuel Johanns, Pascale Lemoine, Virginie Janssens, Giuseppina Grieco, Soren K. Moestrup, Rikke Nielsen, Erik I. Christensen, Pierre J. Courtoy, Hervé Emonard, Etienne Marbaix, Patrick Henriet
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ef8ab5cbd1544d42a3b9b4dc04fabb65
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spelling	oai:doaj.org-article:ef8ab5cbd1544d42a3b9b4dc04fabb652021-12-02T16:08:23ZCellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-210.1038/s41598-017-04648-y2045-2322https://doaj.org/article/ef8ab5cbd1544d42a3b9b4dc04fabb652017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04648-yhttps://doaj.org/toc/2045-2322Abstract 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.Manuel JohannsPascale LemoineVirginie JanssensGiuseppina GriecoSoren K. MoestrupRikke NielsenErik I. ChristensenPierre J. CourtoyHervé EmonardEtienne MarbaixPatrick HenrietNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Manuel Johanns Pascale Lemoine Virginie Janssens Giuseppina Grieco Soren K. Moestrup Rikke Nielsen Erik I. Christensen Pierre J. Courtoy Hervé Emonard Etienne Marbaix Patrick Henriet Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2
description	Abstract 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.
format	article
author	Manuel Johanns Pascale Lemoine Virginie Janssens Giuseppina Grieco Soren K. Moestrup Rikke Nielsen Erik I. Christensen Pierre J. Courtoy Hervé Emonard Etienne Marbaix Patrick Henriet
author_facet	Manuel Johanns Pascale Lemoine Virginie Janssens Giuseppina Grieco Soren K. Moestrup Rikke Nielsen Erik I. Christensen Pierre J. Courtoy Hervé Emonard Etienne Marbaix Patrick Henriet
author_sort	Manuel Johanns
title	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_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_sort	cellular uptake of prommp-2:timp-2 complexes by the endocytic receptor megalin/lrp-2
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ef8ab5cbd1544d42a3b9b4dc04fabb65
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Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2

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