ArticleOncogene2012
Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis.
Article in Oncogene, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 1 of them a synthesis that pooled it.
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Who cites it
27 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.
- Biomarkers of tumor invasiveness in proteomics (Review).International journal of oncology · 2020Pooled it
- Lung endothelial PEAR1 induces tumor cell dormancy.Molecular cancer · 2025Article
- Cathepsins: Emerging targets in the tumor ecosystem to overcome cancers.Seminars in cancer biology · 2025Review
- Cathepsins in cellular entry of human pathogenic viruses.Journal of virology · 2025Review
- Novel insights into the multifaceted and tissue-specific roles of the endocytic receptor LRP1.The Journal of biological chemistry · 2024Review
- A novel Fc-engineered cathepsin D-targeting antibody enhances ADCC, triggers tumor-infiltrating NK cell recruitment, and improves treatment with paclitaxel and enzalutamide in triple-negative breast cancer.Journal for immunotherapy of cancer · 2024Article
- Lysosomal peptidases-intriguing roles in cancer progression and neurodegeneration.FEBS open bio · 2022Review
- Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.Neurobiology of disease · 2021Review
- The Dual Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Atherosclerosis.Frontiers in cardiovascular medicine · 2021Review
- Review
- Neuronal megalin mediates synaptic plasticity-a novel mechanism underlying intellectual disabilities in megalin gene pathologies.Brain communications · 2020Article
- Contribution of the Low-Density Lipoprotein Receptor Family to Breast Cancer Progression.Frontiers in oncology · 2020Review
- Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies.Journal for immunotherapy of cancer · 2019Article
- Developing LRP1 Agonists into a Therapeutic Strategy in Acute Myocardial Infarction.International journal of molecular sciences · 2019Review
- Low Density Receptor-Related Protein 1 Interactions With the Extracellular Matrix: More Than Meets the Eye.Frontiers in cell and developmental biology · 2019Review
- Endothelial LRP1 - A Potential Target for the Treatment of Alzheimer's Disease : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla.Pharmaceutical research · 2017Review
- Identification of LRP-1 as an endocytosis and recycling receptor for β1-integrin in thyroid cancer cells.Oncotarget · 2017Article
- Subcellular Trafficking of Mammalian Lysosomal Proteins: An Extended View.International journal of molecular sciences · 2016Review
- Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition.Arteriosclerosis, thrombosis, and vascular biology · 2016Article
- Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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 (D231N)cath-D, and pro-(D231N)cath-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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