Catalytically inactive human cathepsin D triggers fibroblast invasive growth

Laurent‐Matha, Valérie; Maruani-Herrmann, Sharon; Prébois, Christine; Beaujouin, Mélanie; Glondu, Murielle; Noël, Agnès; Alvarez-Gonzalez, Marie Luz; Blacher, Sylvia; Coopman, Peter J.; Baghdiguian, Stephen; Gilles, Christine; Lončarek, Jadranka; Freiss, Gilles; Vignon, Françoise; Liaudet-Coopman, Emmanuelle

doi:10.1083/jcb.200403078

Cited by 98 publications

(108 citation statements)

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“…Excess M6P prevented pro-cath-D from binding to its M6P receptors and inhibited the internalization of pro-cath-D by 82% ( Figure 1A, panel a, compare lanes 1 and 3). Thus, 18% of pro-cath-D was taken up by HMF fibroblasts in a manner that was independent of the M6P receptors ( Figure 1A, panel a, lane 3), as shown for mouse fibroblasts (Laurent-Matha et al, 2005). Inhibiting LRP1 synthesis with siRNA ( Figure 1A, panel b) led to a 50% decrease in reminiscent pro-cath-D internalization ( Figure 1A, panel a, compare lanes 3 and 4).…”

Section: Resultsmentioning

confidence: 58%

“…We checked these results by investigating the effect of recombinant proteolytically inactive D231N pro-cath-D on the production of endogenous LRP1b-CTF in HMF .1(-) plasmids using Lipofectamine (Gibco-BRL, Life Technologies SAS, Villebon sur Yvette, France). pcDNA3.1(-)cath-D expression plasmid encoding human pre-pro-cath-D has previously been described (Vignon et al, 1986;Glondu et al, 2001Glondu et al, , 2002Berchem et al, 2002;Laurent-Matha et al, 2005;Hu et al, 2008). fibroblasts ( Figure 3C, panel a).…”

Section: Ectopic Cath-d and Pro-cath-d Inhibit Lrp1 Rip In Cos Cells mentioning

confidence: 99%

“…Inhibition of cath-D expression in breast cancer cells decreases tumor growth and metastasis Ohri et al, 2007;Vashishta et al, 2007). Human secreted pro-cath-D stimulates breast cancer cell proliferation (Vignon et al, 1986;Fusek and Vetvicka, 1994;Vetvicka et al, 1994;Ohri et al, 2008), fibroblast outgrowth (Laurent-Matha et al, 2005) and angiogenesis (Hu et al, 2008). We have shown that a mutated catalytically inactive version of cath-D (D231N) is still mitogenic for tumor cells and fibroblasts (Glondu et al, 2001;Berchem et al, 2002;Laurent-Matha et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Human secreted pro-cath-D stimulates breast cancer cell proliferation (Vignon et al, 1986;Fusek and Vetvicka, 1994;Vetvicka et al, 1994;Ohri et al, 2008), fibroblast outgrowth (Laurent-Matha et al, 2005) and angiogenesis (Hu et al, 2008). We have shown that a mutated catalytically inactive version of cath-D (D231N) is still mitogenic for tumor cells and fibroblasts (Glondu et al, 2001;Berchem et al, 2002;Laurent-Matha et al, 2005). We recently discovered that pro-cath-D is the first ligand that binds to the extracellular domain of the b-chain of the LDL receptor-related protein-1 (LRP1) in fibroblasts (Beaujouin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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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: 58%

Section: Ectopic Cath-d and Pro-cath-d Inhibit Lrp1 Rip In Cos Cells mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…5 In addition, it has been suggested that the expression of lysosomal cathepsins are substantially increased in malignant tumours. 6 Furthermore, lysosomal cathepsins can also be produced by stromal fibroblasts and inflammatory cells, which are believed to produce cytokines and proteins that induce the production of cathepsins. The excessive expression and activity of cathepsisns not only helps in promoting tumour growth by increasing the bioavailability of growth factors that reside in the ECM, but also enhances degradation of the ECM components that promote tumour cell invasion, metastasis and the formation of secondary tumours.…”

mentioning

confidence: 99%

Radiation‐induced cathepsin S is involved in radioresistance

Seo

Bae

Lee

2009

Intl Journal of Cancer

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Previous studies have suggested that the production of cathepsin S (CatS), a cysteine protease, was specifically induced in radiationinduced rat mammary tumors. In this study, we further investigate the mechanism by which CatS is induced by radiation and its function. Radiation induced production of CatS at both the mRNA and protein level, and increased its protease activity. In addition, these radiation induced changes occurred in a dose and time-dependent fashion. Agents such as bleomycin, As 2 O 3 and H 2 O 2 , which produce reactive oxygen species (ROS), also induced CatS expression; however, other agents that damage DNA such as taxol and cisplatin did not. Additionally, treatment of the cells with the ROS scavengers, N-acetylcysteine and catalase, inhibited the radiation induced CatS expression. Furthermore, radiationinduced ROS was also involved in IFN-c production, which was responsible for radiation-mediated CatS expression. Moreover, electrophoretic mobility shift assay (EMSA) data obtained using an IFN-stimulated response element (ISRE) oligonucleotide revealed that IFN regulatory factor-1 (IRF1) was the critical transcriptional mediator of IFN-c-dependent CatS production after radiation. Finally, CatS overespression was found to induce radioresistance; however, knockdown of CatS resulted in the suppression of radioresistance. Taken together, the results of this study indicate that radiation induced CatS expression via ROS-IFN-c pathways, and that this increased expression may be involved in radioresistance.

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Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

et al. 2022

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Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.

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Catalytically inactive human cathepsin D triggers fibroblast invasive growth

Cited by 98 publications

References 50 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

Radiation‐induced cathepsin S is involved in radioresistance

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

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