RGD Reference Report - Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2. - Rat Genome Database

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

Authors: 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 
Citation: Johanns M, etal., Sci Rep. 2017 Jun 28;7(1):4328. doi: 10.1038/s41598-017-04648-y.
RGD ID: 13210547
Pubmed: PMID:28659595   (View Abstract at PubMed)
PMCID: PMC5489529   (View Article at PubMed Central)
DOI: DOI:10.1038/s41598-017-04648-y   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
receptor-mediated endocytosis involved_inIDA 13210547PMID:28659595UniProt 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein binding enablesIPIUniProtKB:P3012013210547PMID:28659595UniProt 
protein binding enablesIPIUniProtKB:P3343613210547PMID:28659595UniProt 
protein binding enablesIPIUniProtKB:P9815813210547; 13210547PMID:28659595UniProt 

Objects Annotated

Genes (Rattus norvegicus)
Lrp2  (LDL receptor related protein 2)
Mmp2  (matrix metallopeptidase 2)
Timp1  (TIMP metallopeptidase inhibitor 1)


Additional Information