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Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

Oncogene volume 31, pages 3202–3212 (2012)Cite this article

Abstract

The aspartic protease cathepsin-D (cath-D) is a marker of poor prognosis in breast cancer that is overexpressed and hypersecreted by human breast cancer cells. Secreted pro-cath-D binds to the extracellular domain of the β-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts. The LRP1 receptor has an 85-kDa transmembrane β-chain and a noncovalently attached 515-kDa extracellular α-chain. LRP1 acts by (1) internalizing many ligands via its α-chain, (2) activating signaling pathways by phosphorylating the LRP1β-chain tyrosine and (3) modulating gene transcription by regulated intramembrane proteolysis (RIP) of its β-chain. LRP1 RIP involves two cleavages: the first liberates the LRP1 ectodomain to give a membrane-associated form, LRP1β-CTF, and the second generates the LRP1β-intracellular domain, LRP1β-ICD, that modulates gene transcription. Here, we investigated the endocytosis of pro-cath-D by LRP1 and the effect of pro-cath-D/LRP1β interaction on LRP1β tyrosine phosphorylation and/or LRP1β RIP. Our results indicate that pro-cath-D was partially endocytosed by LRP1 in fibroblasts. However, pro-cath-D and ectopic cath-D did not stimulate phosphorylation of the LRP1β-chain tyrosine. Interestingly, ectopic cath-D and its catalytically inactive D231Ncath-D, and pro-D231Ncath-D all significantly inhibited LRP1 RIP by preventing LRP1β-CTF production. Thus, cath-D inhibits LRP1 RIP independently of its catalytic activity by blocking the first cleavage. As cath-D triggers fibroblast outgrowth by LRP1, we propose that cath-D modulates the growth of fibroblasts by inhibiting LRP1 RIP in the breast tumor microenvironment.

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Acknowledgements

We thank Françoise Berthet and Nadia Kerdjadj for secretarial assistance, and Jean-Yves Cance for the photographs. We also thank Vincent Cavaillès for pertinent suggestions for the gene reporter experiments, Hervé Emonard for helpful discussions and Owen Parkes for English corrections. This work was supported by the Institut National de la Santé et de la Recherche Médicale, University of Montpellier I, ANR Jeunes Chercheuses, Jeunes Chercheurs and the Ligue Nationale contre le Cancer; the Association pour la Recherche sur le Cancer provided a fellowship for Mélanie Beaujouin.

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Authors and Affiliations

  1. IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France

    D Derocq, C Prébois, M Beaujouin, V Laurent-Matha, S Pattingre & E Liaudet-Coopman

  2. INSERM U896, Montpellier, France

    D Derocq, C Prébois, M Beaujouin, V Laurent-Matha, S Pattingre & E Liaudet-Coopman

  3. Université Montpellier1, Montpellier, France

    D Derocq, C Prébois, M Beaujouin, V Laurent-Matha, S Pattingre & E Liaudet-Coopman

  4. CRLC Val d’Aurelle Paul Lamarque, Montpellier, France

    D Derocq, C Prébois, M Beaujouin, V Laurent-Matha, S Pattingre & E Liaudet-Coopman

  5. Screening and Compound Profiling, GlaxoSmithKline, Inc., Research Triangle Park, NC, USA,

    G K Smith

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Derocq, D., Prébois, C., Beaujouin, M. et al. Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis. Oncogene 31, 3202–3212 (2012). https://doi.org/10.1038/onc.2011.501

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