title: Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis.
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.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
authors.forename: D
authors.initials: D
authors.lastname: Derocq
authors.forename: C
authors.initials: C
authors.lastname: Prébois
authors.forename: M
authors.initials: M
authors.lastname: Beaujouin
authors.forename: V
authors.initials: V
authors.lastname: Laurent-Matha
authors.forename: S
authors.initials: S
authors.lastname: Pattingre
authors.forename: G K
authors.initials: GK
authors.lastname: Smith
authors.forename: E
authors.initials: E
authors.lastname: Liaudet-Coopman
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002402:Cathepsin D / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004705:Endocytosis; D004792:Enzyme Precursors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology / Q000473:pathology; D009361:Neoplasm Invasiveness; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D059016:Tumor Microenvironment
chemical_list: D004792:Enzyme Precursors; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D002402:Cathepsin D
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