Abstract
Low-density lipoprotein receptor-related protein-1 (LRP-1) is a multifunctional matricellular receptor composed of a large ligand-binding subunit (515-kDa α-chain) associated with a short trans-membrane subunit (85-kDa β-chain). LRP-1, which exhibits both endocytosis and cell signaling properties, plays a key role in tumor invasion by regulating the activity of proteinases such as matrix metalloproteinases (MMPs). LRP-1 is shed at the cell surface by proteinases such as membrane-type 1 MMP (MT1-MMP) and a disintegrin and metalloproteinase-12 (ADAM-12). Here, we show by using biophysical, biochemical, and cellular imaging approaches that efficient extraction of cell cholesterol and increased LRP-1 shedding occur in MDA-MB-231 breast cancer cells but not in MDA-MB-435 cells. Our data show that cholesterol is differently distributed in both cell lines; predominantly intracellularly for MDA-MB-231 cells and at the plasma membrane for MDA-MB-435 cells. This study highlights the relationship between the rate and cellular distribution of cholesterol and its impact on LRP-1 shedding modulation. Altogether, our data strongly suggest that the increase of LRP-1 shedding upon cholesterol depletion induces a higher accessibility of the sheddase substrate, i.e., LRP-1, at the cell surface rather than an increase of expression of the enzyme.
Highlights
The low-density lipoprotein receptor-related protein-1 (LRP-1) is a large heterodimeric receptor composed of an heavy extracellular chain, the 515-kDa α-chain, non-covalently associated with a light transmembrane chain, the 85-kDa β-chain (Emonard et al, 2014)
We previously reported in the human fibrosarcoma HT1080 cell line the correlation between cell cholesterol amount and efficiency of LRP-1 shedding (Selvais et al, 2011)
In the present study we investigated the relationship between cholesterol cell distribution and LRP-1 shedding efficiency
Summary
The low-density lipoprotein receptor-related protein-1 (LRP-1) is a large heterodimeric receptor composed of an heavy extracellular chain, the 515-kDa α-chain, non-covalently associated with a light transmembrane chain, the 85-kDa β-chain (Emonard et al, 2014). The extracellular α-chain exhibits four cystein-rich complement-type repeats which bind more than 40 ligands, including proteinases and proteinase:inhibitor complexes (Etique et al, 2013). Motifs of the intracellular part of the β-chain activate endocytosis and signaling pathways (Lillis et al, 2005), which drive numerous biological functions and play a key role in the development of many pathological disorders (Lillis et al, 2008; Van Gool et al, 2015). LRP-1 invalidation in mice is lethal at early stage of embryogenesis (Herz et al, 1992). We previously demonstrated that LRP-1 promotes invasion of malignant cells by modulating focal complex composition (Dedieu et al, 2008).
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