Specific Mannose-6-Phosphate Receptor-Independent Sorting of Pro-Cathepsin D in Breast Cancer Cells

Capony, Françoise; Braulke, Thomas; Rougeot, Christian; Roux, Sylvie; Montcourrie, Philippe; Rochefort, Henri

doi:10.1006/excr.1994.1327

Cited by 61 publications

(47 citation statements)

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“…Pro-cath-D is partly endocytosed by LRP1 in fibroblasts Although pro-cath-D is mainly internalized by the mannose-6-phosphate (M6P) receptors (Laurent-Matha et al, 2002, it has been postulated that there are alternative M6P receptor-independent mechanisms (Rijnboutt et al, 1991;Capony et al, 1994;LaurentMatha et al, 2002LaurentMatha et al, , 2005. As we recently reported that pro-cath-D interacts with the extracellular domain of the b-chain of the LRP1 receptor in fibroblasts (Beaujouin et al, 2010), and as LRP1 is an endocytic receptor, we investigated the role of LRP1 in the internalization of secreted pro-cath-D in fibroblasts (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2011

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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 procath-D binds to the extracellular domain of the b-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts. The LRP1 receptor has an 85-kDa transmembrane b-chain and a noncovalently attached 515-kDa extracellular a-chain. LRP1 acts by (1) internalizing many ligands via its a-chain, (2) activating signaling pathways by phosphorylating the LRP1b-chain tyrosine and (3) modulating gene transcription by regulated intramembrane proteolysis (RIP) of its b-chain. LRP1 RIP involves two cleavages: the first liberates the LRP1 ectodomain to give a membrane-associated form, LRP1b-CTF, and the second generates the LRP1b-intracellular domain, LRP1b-ICD, that modulates gene transcription. Here, we investigated the endocytosis of pro-cath-D by LRP1 and the effect of pro-cath-D/LRP1b interaction on LRP1b tyrosine phosphorylation and/or LRP1b 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 LRP1b-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 LRP1b-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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Section: Resultsmentioning

confidence: 99%

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

et al. 2011

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“…Lysosomal targeting is mediated by two M6P-receptors (cation-dependent 46 kDa and cationindependent 300 kDa M6PR) [2,5]. Another way to target pCD to lysosomes is independent of the M6P tag and is not yet fully understood but the role of sphingolipid activator precursor protein prosaposin was suggested [6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

532

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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“…Human cath-D catalytic sites include two critical aspartic residues (amino acid 33 and 231) located on the 14 kDa and 34 kDa chains, respectively [18]. Depending on the cell type, cath-D may also be targeted to lysosomes in a M6P-independent manner [33,34]. The intermediate 48 kDa single-chain species is then cleaved in lysosomes into a mature two-chain enzyme consisting of a light (14 kDa) amino-terminal domain and a heavy (34 kDa) carboxyl-terminal domain.…”

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confidence: 99%

Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis

et al. 2006

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Specific Mannose-6-Phosphate Receptor-Independent Sorting of Pro-Cathepsin D in Breast Cancer Cells

Cited by 61 publications

References 0 publications

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

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

Cathepsin D—Many functions of one aspartic protease

Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis

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