Pro-cathepsin D interacts with the extracellular domain of the {beta} chain of LRP1 and promotes LRP1-dependent fibroblast outgrowth.: cath-D, LRP1 and fibroblast outgrowth

Abstract : Interactions between cancer cells and fibroblasts are crucial in cancer progression. We have previously shown that the aspartic protease cathepsin D (cath-D), a marker of poor prognosis in breast cancer that is overexpressed and highly secreted by breast cancer cells, triggers mouse embryonic fibroblast outgrowth via a paracrine loop. Here, we show the requirement of secreted cath-D for human mammary fibroblast outgrowth using a three-dimensional co-culture assay with breast cancer cells that do or do not secrete pro-cath-D. Interestingly, proteolytically-inactive pro-cath-D remains mitogenic, indicating a mechanism involving protein-protein interaction. We identify the low-density lipoprotein (LDL) receptor-related protein-1, LRP1, as a novel binding partner for pro-cath-D in fibroblasts. Pro-cath-D binds to residues 349-394 of the β chain of LRP1, and is the first ligand of the extracellular domain of LRP1β to be identified. We show that pro-cath-D interacts with LRP1β in cellulo. Interaction occurs at the cell surface, and overexpressed LRP1β directs pro-cath-D to the lipid rafts. Our results reveal that the ability of secreted pro-cath-D to promote human mammary fibroblast outgrowth depends on LRP1 expression, suggesting that pro-cath-D-LRP1β interaction plays a functional role in the outgrowth of fibroblasts. Overall, our findings strongly suggest that pro-cath-D secreted by epithelial cancer cells promotes fibroblast outgrowth in a paracrine LRP1-dependent manner in the breast tumor microenvironment.
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Article dans une revue
Journal of Cell Science, Company of Biologists, 2010, 123 (19), pp.3336-3346. 〈10.1242/jcs.070938〉
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Mélanie Beaujouin, Christine Prébois, Danielle Derocq, Valérie Laurent-Matha, Olivier Masson, et al.. Pro-cathepsin D interacts with the extracellular domain of the {beta} chain of LRP1 and promotes LRP1-dependent fibroblast outgrowth.: cath-D, LRP1 and fibroblast outgrowth. Journal of Cell Science, Company of Biologists, 2010, 123 (19), pp.3336-3346. 〈10.1242/jcs.070938〉. 〈inserm-00518213〉

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