Erratum: Control of ADAM17 activity by regulation of its cellular localisation

Lorenzen, Inken; Lokau, Juliane; Korpys, Yvonne; Oldefest, Mirja; Flynn, Charlotte M.; Künzel, Ulrike; Garbers, Christoph; Freeman, Matthew; Grötzinger, Joachim; Düsterhöft, Stefan

doi:10.1038/srep37364

Cited by 8 publications

(3 citation statements)

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“…Of note, the whole enriched material released by the cells in different conditions was subjected to SDS‐PAGE, and thus observed expression levels mainly correlate with the extent of EV release rather than changes in EV protein composition. In concordance with previous publications (Blanchot‐Jossic et al., 2005 ; Groth et al., 2016 ; Lorenzen et al., 2016 ; McGowan et al., 2007 ; Schlöndorff et al., 2000 ), we identified the pro‐form (immature) of ADAM17 at a size of approx. 110−120 kDa in cell lysates, and a mature form—lacking the inhibitory pro‐domain—at a size of approx.…”

Section: Resultssupporting

confidence: 92%

Chemotherapy‐induced release of ADAM17 bearing EV as a potential resistance mechanism in ovarian cancer

Hugendieck

Lettau

Andreas

et al. 2023

J of Extracellular Vesicle

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Ovarian cancer (OvCa) is the gynaecological disorder with the poorest prognosis due to the fast development of chemoresistance. We sought to connect chemoresistance and cancer cell-derived extracellular vesicles (EV). The mechanisms of how chemoresistance is sustained by EV remained elusive. One potentially contributing factor is A Disintegrin and Metalloprotease 17 (ADAM17)-itself being able to promote chemoresistance and inducing tumour cell proliferation and survival via the Epidermal Growth Factor Receptor (EGFR) pathway by shedding several of its ligands including Amphiregulin (AREG). We now demonstrate that upon chemotherapeutic treatment, proteolytically active ADAM17 is released in association with EV from OvCa cells. In terms of function, we show that patient-derived EV induce AREG shedding and restore chemoresistance in ADAM17-deficient cells. Confirming that ADAM17-containing EV transmit chemoresistance in OvCa, we propose that ADAM17 levels (also on EV) might serve as an indicator for tumour progression and the chemosensitivity status of a given patient.

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Section: Resultssupporting

confidence: 92%

Chemotherapy‐induced release of ADAM17 bearing EV as a potential resistance mechanism in ovarian cancer

Hugendieck

Lettau

Andreas

et al. 2023

J of Extracellular Vesicle

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“…Fig. 2G) [ 13 , 31 , 35 ]. Both the C- and the N-terminal antibody detected the same time-dependent decrease of mature ADAM10 in the lysates after GI pretreatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

The metalloproteinase ADAM10 requires its activity to sustain surface expression

Seifert¹,

Düsterhöft²,

Wozniak³

et al. 2020

Cell. Mol. Life Sci.

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The metalloproteinase ADAM10 critically contributes to development, inflammation, and cancer and can be controlled by endogenous or synthetic inhibitors. Here, we demonstrate for the first time that loss of proteolytic activity of ADAM10 by either inhibition or loss of function mutations induces removal of the protease from the cell surface and the whole cell. This process is temperature dependent, restricted to mature ADAM10, and associated with an increased internalization, lysosomal degradation, and release of mature ADAM10 in extracellular vesicles. Recovery from this depletion requires de novo synthesis. Functionally, this is reflected by loss and recovery of ADAM10 substrate shedding. Finally, ADAM10 inhibition in mice reduces systemic ADAM10 levels in different tissues. Thus, ADAM10 activity is critically required for its surface expression in vitro and in vivo. These findings are crucial for development of therapeutic ADAM10 inhibition strategies and may showcase a novel, physiologically relevant mechanism of protease removal due to activity loss.

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“…GSH can enter the cell through endocytosis/pinocytosis, transcytosis, and in the shape of GSHprotein conjugates (51), which could allow an interaction with the ADAM17 ectodomain even when it is not apically localized. Mature ADAM17 is localized mainly intracellularly, and only a small fraction is localized at the cell surface (33). We have shown previously (53) that cigarette smoke-induced interactions between ADAM17 and its substrates occur intracellularly in polarized airway cells.…”

Section: L564mentioning

confidence: 67%

Extracellular oxidation in cystic fibrosis airway epithelium causes enhanced EGFR/ADAM17 activity

Stolarczyk

Veit

Schnúr

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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The EGF receptor (EGFR)/a disintegrin and metalloproteinase 17 (ADAM17) signaling pathway mediates the shedding of growth factors and secretion of cytokines and is involved in chronic inflammation and tissue remodeling. Since these are hallmarks of cystic fibrosis (CF) lung disease, we hypothesized that CF transmembrane conductance regulator (CFTR) deficiency enhances EGFR/ADAM17 activity in human bronchial epithelial cells. In CF bronchial epithelial CFBE41o cells lacking functional CFTR (iCFTR) cultured at air-liquid interface (ALI) we found enhanced ADAM17-mediated shedding of the EGFR ligand amphiregulin (AREG) compared with genetically identical cells with induced CFTR expression (iCFTR). Expression of the inactive G551D-CFTR did not have this effect, suggesting that active CFTR reduces EGFR/ADAM17 activity. This was confirmed in CF compared with normal differentiated primary human bronchial epithelial cells (HBEC-ALI). ADAM17-mediated AREG shedding was tightly regulated by the EGFR/MAPK pathway. Compared with iCFTR cells, iCFTR cells displayed enhanced apical presentation and phosphorylation of EGFR, in accordance with enhanced EGFR/ADAM17 activity in CFTR-deficient cells. The nonpermeant natural antioxidant glutathione (GSH) strongly inhibited AREG release in iCFTR and in primary HBEC-ALI, suggesting that ADAM17 activity is directly controlled by extracellular redox potentials in differentiated airway epithelium. Furthermore, the fluorescent redox probe glutaredoxin 1-redox-sensitive green fluorescent protein-glycosylphosphatidylinositol (Grx1-roGFP-GPI) indicated more oxidized conditions in the extracellular space of iCFTR cells, consistent with the role of CFTR in GSH transport. Our data suggest that in CFTR-deficient airway epithelial cells a more oxidized state of the extracellular membrane, likely caused by defective GSH secretion, leads to enhanced activity of the EGFR/ADAM17 signaling axis. In CF lungs this could contribute to tissue remodeling and hyperinflammation.

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Erratum: Control of ADAM17 activity by regulation of its cellular localisation

Abstract: Scientific Reports 6: Article number: 35067; published online: 12 October 2016; updated: 21 November 2016.

Cited by 8 publications

References 0 publications

Chemotherapy‐induced release of ADAM17 bearing EV as a potential resistance mechanism in ovarian cancer

Chemotherapy‐induced release of ADAM17 bearing EV as a potential resistance mechanism in ovarian cancer

The metalloproteinase ADAM10 requires its activity to sustain surface expression

Extracellular oxidation in cystic fibrosis airway epithelium causes enhanced EGFR/ADAM17 activity

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