Cleavage of Nidogen-1 by Cathepsin S Impairs Its Binding to Basement Membrane Partners

Sage, Juliette; Leblanc-Noblesse, Emmanuelle; Nizard, Carine; Sasaki, Takako; Schnebert, Sylvianne; Perrier, Éric; Kurfürst, Robin; Brὂmme, Dieter; Lalmanach, Gilles; Lecaille, Fabien

doi:10.1371/journal.pone.0043494

Cited by 37 publications

(27 citation statements)

References 54 publications

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“…Hereby, we were able to verify the findings by Sage et al showing that nidogen-1 is cleaved by CatS at amino acid position 693 (NH 3 -…HERE 693 ) which is located in the thyroglobulin-like (Tg) domain adjacent to the G3 domain [19].…”

Section: Discussionsupporting

confidence: 83%

Nidogen-1 Degraded by Cathepsin S can be Quantified in Serum and is Associated with Non–Small Cell Lung Cancer

et al. 2017

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Loss of basement membrane (BM) integrity is typically associated with cancer. Nidogen-1 is an essential component of the BM. Nidogen-1 is a substrate for cathepsin-S (CatS) which is released into the tumor microenvironment. Measuring nidogen-1 degraded by CatS may therefore have biomarker potential in cancer. The aim of this study was to investigate if CatS-degraded nidogen-1 was detectable in serum and a possible biomarker for cancer, a pathology associated with disruption of the BM. A competitive enzyme-linked immunosorbent assay (NIC) was developed with a monoclonal mouse antibody specific for a CatS cleavage site on human nidogen-1. Dilution and spiking recovery, inter- and intravariation, as well as accuracy were evaluated. Serum levels were evaluated in patients with breast cancer, small cell lung cancer (SCLC), and non-SCLC (NSCLC) and in healthy controls. The results indicated that the NIC assay was specific for nidogen-1 cleaved by CatS. Inter- and intraassay variations were 9% and 14%, respectively. NIC was elevated in NSCLC as compared to healthy controls (P < .001), breast cancer (P < .01), and SCLC (P < .5). The diagnostic power (area under the receiver operating characteristics) of NIC for NSCLC as compared to all other samples combined was 0.83 (95% confidence interval: 0.71-0.95), P < .0001. In conclusion, nidogen-1 degraded by CatS can be quantified in serum by the NIC assay. The current data strongly suggest that cathepsin-S degradation of nidogen-1 is strongly associated with NSCLC, which needs validation in larger clinical cohorts.

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Section: Discussionsupporting

confidence: 83%

Nidogen-1 Degraded by Cathepsin S can be Quantified in Serum and is Associated with Non–Small Cell Lung Cancer

et al. 2017

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“…The majority of identified substrates were not previously reported to be cleaved by cathepsins. However, several of the identified ECM components were previously shown to be cathepsin substrates (fibronectin, laminin, tenascin, collagen, nidogen, and perlecan (1,36,37)), validating our approach as a means to study cathepsin-mediated substrate shedding. A number of the identified substrates share a high degree of similarity and closely related family members of substrates were identified in different cell lines (neuropilin 2, ephrin type B receptor 4).…”

Section: Cathepsins S and L Shed Several Membrane-anchored Proteins Fsupporting

confidence: 52%

Proteomic Identification of Cysteine Cathepsin Substrates Shed from the Surface of Cancer Cells

Sobotič

Vizovišek

Vidmar

et al. 2015

Molecular & Cellular Proteomics

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Extracellular cysteine cathepsins are known to drive cancer progression, but besides degradation of extracellular matrix proteins little is known about their physiological substrates and thus the molecular mechanisms they deploy. One of the major mechanisms used by other extracellular proteases to facilitate cancer progression is proteolytic release of the extracellular domains of transmembrane proteins or ectodomain shedding. Here we show using a mass spectrometry-based approach that cathepsins L and S act as sheddases and cleave extracellular domains of CAM adhesion proteins and transmembrane receptors from the surface of cancer cells. In cathepsin S-deficient mouse pancreatic cancers, processing of these cathepsin substrates is highly reduced, pointing to an essential role of cathepsins in extracellular shedding. In addition to influencing cell migration and invasion, shedding of surface proteins by extracellular cathepsins impacts intracellular signaling as demonstrated for regulation of Ras GTPase activity, thereby providing a putative mechanistic link between extracellular cathepsin activity and cancer progression. The MS data is available via ProteomeXchange with identifier PXD002192. Molecular & Cellular Proteomics

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“…Gene network analysis identified down-regulation of laminin beta 1 (LAMB1) and alpha 2 (LAMA2), nidogen-1 (NID1) and COL6A3, and increased expression of the protease cathepsin S (CTSS), all of which would reflect endothelial damage or BM dismantling as part of EndoMT (Lakatta and Levy, 2003;Li and Bertram, 2010). Breakdown of NID1, LAMB, COL and elastin by CTSS has been shown to impair BM integrity and stability (Sage et al, 2012;Turk et al, 2012). Increased expression of CTSK and CTSS has been reported in human MMVD, and cyclic strain increases CTSK expression in sheep mitral valve myofibroblasts (Rabkin et al, 2001;Aikawa et al, 2006;Lacerda et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Gene network and canonical pathway analysis in canine myxomatous mitral valve disease: A microarray study

Liu

Culshaw

et al. 2015

The Veterinary Journal

112

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Myxomatous mitral valve disease (MMVD) is the single most common acquired heart disease of the dog and is particularly common in small pedigree breed dogs such as the Cavalier King Charles spaniel (CKCS). There are limited data on the mitral valve transcriptome and the aim of this study was to use the microarray technology in conjunction with bioinformatics platforms to analyse transcript changes in MMVD in CKCS compared to normal dogs (non-CKCS). Differentially expressed genes (n = 5397) were identified using cut-off settings of fold change, false discovery rate (FDR) and P <0.05. In total, 4002 genes were annotated to a specific transcript in the Affymetrix canine database, and after further filtering, 591 annotated canine genes were identified: 322 (55%) were up-regulated and 269 (45%) were down-regulated. Canine microRNAs (cfa-miR; n = 59) were also identified. Gene ontology and network analysis platforms identified between six and 10 significantly different biological function clusters from which the following were selected as relevant to MMVD: inflammation, cell movement, cardiovascular development, extracellular matrix organisation and epithelial-to-mesenchymal (EMT) transition. Ingenuity Pathway Analysis identified three canonical pathways relevant to MMVD: caveolar-mediated endocytosis, remodelling of epithelial adherens junctions, and endothelin-1 signalling. Considering the biological relevance to MMVD, the gene families of importance with significant difference between groups included collagens, ADAMTS peptidases, proteoglycans, matrix metalloproteinases (MMPs) and their inhibitors, basement membrane components, cathepsin S, integrins, tight junction cell adhesion proteins, cadherins, other matrix-associated proteins, and members of the serotonin (5-HT)/transforming growth factor -β signalling pathway.

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Cleavage of Nidogen-1 by Cathepsin S Impairs Its Binding to Basement Membrane Partners

Cited by 37 publications

References 54 publications

Nidogen-1 Degraded by Cathepsin S can be Quantified in Serum and is Associated with Non–Small Cell Lung Cancer

Nidogen-1 Degraded by Cathepsin S can be Quantified in Serum and is Associated with Non–Small Cell Lung Cancer

Proteomic Identification of Cysteine Cathepsin Substrates Shed from the Surface of Cancer Cells

Gene network and canonical pathway analysis in canine myxomatous mitral valve disease: A microarray study

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