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Salt-Mediated Nanopore Detection of ADAM-17.

ABSTRACT: ADAM-17 (a disintegrin and metalloproteinase 17) plays an important role in various physiological and pathophysiological processes. Overexpression/underexpression of ADAM-17 could lead to various diseases. In this work, by taking advantage of ionic strength and salt gradient, and monitoring the cleavage of a substrate peptide by ADAM-17 in a nanopore, we developed a label-free sensor for the rapid detection of ADAM-17. The sensor was highly sensitive and selective: picomolar concentrations of ADAM-17 could be detected within minutes, while structure similar proteases such as ADAM-9 and MMP-9 did not interfere with its detection. Our developed nanopore sensing strategy should find useful applications in the development of nanopore sensors for other proteases of biological, pharmaceutical, and medical importance.

SUBMITTER: Chen X

PROVIDER: S-EPMC7288862 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Salt-Mediated Nanopore Detection of ADAM-17.

Chen Xiaohan X Zhang Youwen Y Roozbahani Golbarg Mohammadi GM Guan Xiyun X

ACS applied bio materials 20181224 1

ADAM-17 (a disintegrin and metalloproteinase 17) plays an important role in various physiological and pathophysiological processes. Overexpression/underexpression of ADAM-17 could lead to various diseases. In this work, by taking advantage of ionic strength and salt gradient, and monitoring the cleavage of a substrate peptide by ADAM-17 in a nanopore, we developed a label-free sensor for the rapid detection of ADAM-17. The sensor was highly sensitive and selective: picomolar concentrations of AD ...[more]

PMID: 32529174

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Iron-Overload triggers ADAM-17 mediated inflammation in Severe Alcoholic Hepatitis.

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| S-EPMC6035223 | biostudies-literature

ADAM-17: the enzyme that does it all.

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A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma.

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Src and ADAM-17-mediated shedding of transforming growth factor-alpha is a mechanism of acute resistance to TRAIL.

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Cyclooxygenase-2 activates EGFR-ERK1/2 pathway via PGE2-mediated ADAM-17 signaling in testosterone-induced benign prostatic hyperplasia.

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| S-EPMC9958186 | biostudies-literature

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The enhanced susceptibility of ADAM-17 hypomorphic mice to DSS-induced colitis is not ameliorated by loss of RIPK3, revealing an unexpected function of ADAM-17 in necroptosis.

Project description:The disintegrin metalloprotease ADAM17 has a critical role in intestinal inflammation and regeneration in mice, as illustrated by the dramatically increased susceptibility of ADAM17 hypomorphic (ADAM17ex/ex) mice to dextran sulfate sodium (DSS)-induced colitis. Similarly, necroptosis has been implicated in inflammatory responses in the intestine. In this study, we have investigated the contribution of necroptosis to ADAM17-regulated intestinal inflammation in vivo by crossing ADAM17ex/ex mice with mice that lack the necroptotic core protein RIPK3. Despite the loss of RIPK3, ADAM17ex/ex/RIPK3-/- mice showed the same increased susceptibility as ADAM17ex/ex mice in both acute and chronic models of DSS-induced colitis. Mice of both genotypes revealed comparable results with regard to weight loss, disease activity index and colitis-associated changes of inner organs. Histopathological analyses confirmed similar tissue destruction, loss of barrier integrity, immune cell infiltration, and cell death; serum analyses revealed similar levels of the pro-inflammatory cytokine KC. Resolving these unexpected findings, ADAM17ex/ex mice did not show phosphorylation of RIPK3 and its necroptotic interaction partner MLKL during DSS-induced colitis, although both proteins were clearly expressed. Consistent with these findings, murine embryonic fibroblasts derived from ADAM17ex/ex mice were protected from tumor necrosis factor (TNF)-induced necroptosis and failed to show phosphorylation of MLKL and RIPK3 after induction of necroptosis by TNF, revealing a novel, undescribed role of the protease ADAM17 in necroptosis.

| S-EPMC5849186 | biostudies-literature

ADAM-17 regulates endothelial cell morphology, proliferation, and in vitro angiogenesis.

Project description:Modulation of angiogenesis is a promising approach for treating a wide variety of human diseases including ischemic heart disease and cancer. In this study, we show that ADAM-17 is an important regulator of several key steps during angiogenesis. Knocking down ADAM-17 expression using lentivirus-delivered siRNA in HUVECs inhibited cell proliferation and the ability of cells to form close contact in two-dimensional cultures. Similarly, ADAM-17 depletion inhibited the ability of HUVECs to form capillary-like networks on top of three-dimensional Matrigel as well as in co-culture with fibroblasts within a three-dimensional scaffold. In mechanistic studies, both baseline and VEGF-induced MMP-2 activation and Matrigel invasion were inhibited by ADAM-17 depletion. Based on our findings we propose that ADAM-17 is part of a novel pro-angiogenic pathway leading to MMP-2 activation and vessel formation.

| S-EPMC2875258 | biostudies-other

ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation.

Project description:Tumour growth is not solely driven by tumour cell-intrinsic mechanisms, but also depends on paracrine signals provided by the tumour micro-environment. These signals comprise cytokines and growth factors that are synthesized as trans-membrane proteins and need to be liberated by limited proteolysis also termed ectodomain shedding. Members of the family of A disintegrin and metalloproteases (ADAM) are major mediators of ectodomain shedding and therefore initiators of paracrine signal transduction. In this review, we summarize the current knowledge on how ADAM proteases on tumour cells but also on cells of the tumour micro-environment contribute to the formation of gastrointestinal tumours, and discuss how these processes can be exploited pharmacologically.

| S-EPMC7404302 | biostudies-literature

Chemotherapy-induced activation of ADAM-17: a novel mechanism of drug resistance in colorectal cancer.

Project description:PurposeWe have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a disintegrin and metalloproteinases) and soluble growth factors in this acute drug resistance mechanism.Experimental designIn vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting.ResultsChemotherapy (5-fluorouracil) treatment resulted in acute increases in transforming growth factor-alpha, amphiregulin, and heregulin ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. Small interfering RNA-mediated silencing and pharmacologic inhibition confirmed that ADAM-17 was the principal ADAM involved in this prosurvival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumor growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of human epidermal receptors but also increased the activity of a number of other growth factor receptors, such as insulin-like growth factor-I receptor and vascular endothelial growth factor receptor.ConclusionsChemotherapy acutely activates ADAM-17, which results in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. Thus, pharmacologic inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC.

| S-EPMC2896550 | biostudies-literature

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