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.
Highlights
Matrix metalloproteinases (MMPs) compose a family of Zn2+-dependent endoproteases that display a large variety of substrates including extracellular matrix macromolecules, cell-surface receptors, growth factors, cytokines and chemokines[1]
We first examined whether proMMP-2 and/or its complex with tissue inhibitors of metalloproteinases (TIMPs)-2 could represent a new ligand for megalin/lipoprotein receptor-related proteins (LRPs)-2
We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex
Summary
Matrix metalloproteinases (MMPs) compose a family of Zn2+-dependent endoproteases that display a large variety of substrates including extracellular matrix macromolecules, cell-surface receptors, growth factors, cytokines and chemokines[1]. These proteinases play important roles in physiological processes, such as wound repair[2] and cyclic endometrial remodeling[3], as well as in the development of various pathologies including cancer[4]. Extracellular levels of certain MMPs are regulated by selective internalization and intracellular degradation In this regard, low-density lipoprotein receptor-related proteins (LRPs) compose a family of endocytic and signaling receptors that exert their activities on a large variety of molecules including proteolytic enzymes[6]. We evaluated the physiological relevance of proMMP-2 and TIMP-2 uptake in transgenic mice undergoing renal invalidation of megalin/LRP-217
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