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ADAM17

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https://www.readbyqxmd.com/read/28297575/selective-inhibition-of-adam17-efficiently-mediates-glycoprotein-ib%C3%AE-retention-during-ex-vivo-generation-of-human-induced-pluripotent-stem-cell-derived-platelets
#1
Shinji Hirata, Takahiko Murata, Daisuke Suzuki, Sou Nakamura, Ryoko Jono-Ohnishi, Hidenori Hirose, Akira Sawaguchi, Satoshi Nishimura, Naoshi Sugimoto, Koji Eto
Donor-independent platelet concentrates for transfusion can be produced in vitro from induced pluripotent stem cells (iPSCs). However, culture at 37°C induces ectodomain shedding on platelets of glycoprotein Ibα (GPIbα), the von Willebrand factor receptor critical for adhesive function and platelet lifetime in vivo, through temperature-dependent activation of a disintegrin and metalloproteinase 17 (ADAM17). The shedding can be suppressed by using inhibitors of panmetalloproteinases and possibly of the upstream regulator p38 mitogen-activated protein kinase (p38 MAPK), but residues of these inhibitors in the final platelet products may be accompanied by harmful risks that prevent clinical application...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28274635/identification-of-novel-tace-inhibitors-compatible-with-topical-application
#2
Gilles Ouvry, Yaël Berton, Yushma Bhurruth-Alcor, Laetitia Bonnary, Claire Bouix-Peter, Karine Bouquet, Marilyne Bourotte, Sandrine Chambon, Catherine Comino, Benoît Deprez, Denis Duvert, Gwenaëlle Duvert, Feriel Hacini-Rachinel, Craig S Harris, Anne-Pascale Luzy, Arnaud Mathieu, Corinne Millois, Jonathan Pascau, Artur Pinto, Gaëlle Polge, Arnaud Reitz, Kevin Reversé, Carine Rosignoli, Nathalie Taquet, Laurent F Hennequin
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors...
February 20, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28264989/characterization-of-the-catalytic-properties-of-the-membrane-anchored-metalloprotease-adam9-in-cell-based-assays
#3
Thorsten Maretzky, Steven Swendeman, Elin Mogollon, Gisela Weskamp, Umut Sahin, Karina Reiss, Carl P Blobel
ADAM9 (a disintegrin and metalloprotease9) is a membrane-anchored metalloproteinase that has been implicated in pathological retinal neovascularization and in tumor progression. ADAM9 has constitutive catalytic activity in both biochemical and cell-based assays and can cleave several membrane proteins, including Epidermal-Growth-Factor and Ephrin receptor B4. Yet, little is currently known about the catalytic properties of ADAM9 and its posttranslational regulation and inhibitor profile in cell-based assays...
March 6, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28249164/baff-and-taci-dependent-processing-of-baffr-by-adam-proteases-regulates-the-survival-of-b-cells
#4
Cristian R Smulski, Patrick Kury, Lea M Seidel, Hannah S Staiger, Anna K Edinger, Laure Willen, Maximilan Seidl, Henry Hess, Ulrich Salzer, Antonius G Rolink, Marta Rizzi, Pascal Schneider, Hermann Eibel
B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing...
February 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/28245631/role-of-nerve-growth-factor-ngf-and-mirnas-in-epithelial-ovarian-cancer
#5
REVIEW
Rocío Retamales-Ortega, Lorena Oróstica, Carolina Vera, Paula Cuevas, Andrea Hernández, Iván Hurtado, Margarita Vega, Carmen Romero
Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression...
February 26, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28161636/diallyl-trisulfide-a-chemopreventive-agent-from-allium-vegetables-inhibits-alpha-secretases-in-breast-cancer-cells
#6
Violet A Kiesel, Silvia D Stan
Breast cancer affects one in eight women throughout the course of their lifetime creating a demand for novel prevention strategies against this disease. The Notch signaling pathway is often aberrantly activated in human malignancies including breast cancer. Alpha secretases, including ADAM (A Disintegrin and Metalloprotease) -10 and -17, are proteases that play a key role in the cleavage of cell surface molecules and subsequent ligand-mediated activation of Notch signaling pathway. High expression levels of ADAM10 and 17 have been clinically associated with a lower disease-free survival in breast cancer patients...
February 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28160627/interleukin-11-driven-gastric-tumourigenesis-is-independent-of-trans-signalling
#7
Jesse J Balic, Christoph Garbers, Stefan Rose-John, Liang Yu, Brendan J Jenkins
Deregulated gp130-dependent STAT3 signalling by the pleiotropic cytokine interleukin (IL)-11 has been implicated in the pathogenesis of gastric cancer (GC), the third most common cancer worldwide. While the IL-11-gp130-STAT3 signalling axis has traditionally been thought to exclusively use the membrane-bound IL-11 receptor (mIL-11R), recent evidence suggests that mIL-11R can be proteolytically cleaved to generate a soluble form (sIL-11R) which can elicit trans-signalling. Since the role of IL-11 trans-signalling in disease pathogenesis is unknown, here we have employed the IL-11-driven gp130(F/F) spontaneous model of GC to determine whether IL-11 trans-signalling promotes gastric tumourigenesis...
February 1, 2017: Cytokine
https://www.readbyqxmd.com/read/28143719/enhancing-interleukin-6-and-interleukin-11-receptor-cleavage
#8
Juliane Lokau, Marieke Wandel, Christoph Garbers
Proteolytic cleavage of the membrane-bound Interleukin-6 receptor (IL-6R) by the metalloprotease ADAM17 releases an agonistic soluble form of the IL-6R (sIL-6R), which is responsible for the pro-inflammatory trans-signaling branch of the cytokine's activities. This proteolytic step, which is also called ectodomain shedding, is critically regulated by the cleavage site within the IL-6R stalk, because mutations or small deletions within this region are known to render the IL-6R irresponsive towards proteolysis...
January 29, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28122773/adam17-a-molecular-switch-to-control-tnfr2-during-atherogenesis-in-vivo
#9
EDITORIAL
Yiting Jia, Wei Kong
No abstract text is available yet for this article.
February 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28112251/corrigendum-adam17-egfr-axis-promotes-transglutaminase-dependent-skin-barrier-formation-through-phospholipase-c-%C3%AE-1-and-protein-kinase-c-pathways
#10
Cristina Wolf, Yawen Qian, Matthew A Brooke, David P Kelsell, Claus-Werner Franzke
No abstract text is available yet for this article.
January 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28109308/semaphorin-7a-as-a-potential-immune-regulator-and-promising-therapeutic-target-in-rheumatoid-arthritis
#11
Jianmin Xie, Hao Wang
BACKGROUND: Semaphorin 7A (Sema7A) is expressed by several different classes of lymphoid and myeloid cells and is a potent immunomodulator. We examined the role of Sema7A in modulating cellular immune responses and to provide experimental data validating the therapeutic potential of Sema7A in rheumatoid arthritis (RA). METHODS: Soluble Sema7A (sSema7A) levels in the serum and synovial fluid from patients with RA or osteoarthritis, as well as cytokine secretions, were analyzed with an enzyme-linked immunosorbent assay...
January 21, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28107420/the-polyherbal-wattana-formula-displays-anti-amyloidogenic-properties-by-increasing-%C3%AE-secretase-activities
#12
Htut Htut Htoo, Suveerawan Limsuvan, Onusa Thamsermsang, Jean-François Hernandez, Frédéric Checler, Piyarat Govitrapong, Narawut Pakaprot, Pravit Akarasereenont, Bruno Vincent
Alzheimer's disease is characterized by the deposition of insoluble amyloid-β peptides produced from the β-amyloid precursor protein (βAPP). Because α-secretase cleavage by ADAM10 and ADAM17 takes place in the middle of Aβ, its activation is considered as a promising anti-AD therapeutic track. Here we establish that the polyherbal Wattana formula (WNF) stimulates sAPPα production in cells of neuronal and non-neuronal origins through an increase of both ADAM10 and ADAM17 catalytic activities with no modification of BACE1 activity and expression...
2017: PloS One
https://www.readbyqxmd.com/read/28106546/a-common-variant-of-il-6r-is-associated-with-elevated-il-6-pathway-activity-in-alzheimer-s-disease-brains
#13
Patrick C G Haddick, Jessica L Larson, Nisha Rathore, Tushar R Bhangale, Qui T Phung, Karpagam Srinivasan, David V Hansen, Jennie R Lill, Margaret A Pericak-Vance, Jonathan Haines, Lindsay A Farrer, John S Kauwe, Gerard D Schellenberg, Carlos Cruchaga, Alison M Goate, Timothy W Behrens, Ryan J Watts, Robert R Graham, Joshua S Kaminker, Marcel van der Brug
The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner...
January 18, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28104813/structural-modeling-defines-transmembrane-residues-in-adam17-that-are-crucial-for-rhbdf2-adam17-dependent-proteolysis
#14
Xue Li, Thorsten Maretzky, Jose Manuel Perez-Aguilar, Sébastien Monette, Gisela Weskamp, Sylvain Le Gall, Bruce Beutler, Harel Weinstein, Carl P Blobel
A disintegrin and metalloproteinase 17 (ADAM17) controls the release of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) and is crucial for protecting the skin and intestinal barrier by proteolytic activation of Epidermal growth factor receptor (EGFR)-ligands. The seven-membrane spanning inactive Rhomboid2 (iRhom2; Rhbdf2) is required for ADAM17-dependent TNFα shedding and crosstalk with the EGFR, and a point mutation (sinecure, sin) in the first transmembrane domain (TMD) of Rhbdf2 (Rhbdf2(sin)) blocks TNFα shedding, yet little is known about the underlying mechanism...
January 19, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28063160/elevated-semaphorin5a-in-systemic-lupus-erythematosus-is-in-association-with-disease-activity-and-lupus-nephritis
#15
Y Du, X Wu, M Chen, W Wang, W Xv, L Ye, D Wu, J Xue, W Sun, J Luo, H Wu
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by extensive immune response, including over-activation of T and B cell development of pathogenic autoantibodies, organ damage induced by the formation and deposition of immune complex and the abnormal elevation of type I interferon. Semaphorin5A (Sema5A) is involved essentially in immune cell regulation and is also implicated in the pathogenesis of autoimmune disorders. We aimed to evaluate the role of Sema5A in patients with SLE. Serum levels of Sema5A were tested by enzyme-linked immunosorbent assay (ELISA) in 152 SLE patients and 48 healthy controls...
January 7, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28062509/adam17-deficiency-promotes-atherosclerosis-by-enhanced-tnfr2-signaling-in-mice
#16
Alexandros Nicolaou, Zhen Zhao, Bernd H Northoff, Kristina Sass, Andreas Herbst, Alexander Kohlmaier, Athena Chalaris, Christian Wolfrum, Christian Weber, Sabine Steffens, Stefan Rose-John, Daniel Teupser, Lesca M Holdt
OBJECTIVE: ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase releasing different types of membrane-bound proteins, including adhesion molecules, cytokines, and their receptors as well as inflammatory mediators. Because these substrates modulate important mechanisms of atherosclerosis, we hypothesized that ADAM17 might be involved in the pathogenesis of this frequent disease. APPROACH AND RESULTS: Because Adam17-knockout mice are not viable, we studied the effect of Adam17 deficiency on atherosclerosis in Adam17 hypomorphic mice (Adam17(ex/ex)), which have low residual Adam17 expression...
December 22, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28060820/proteolytic-origin-of-the-soluble-human-il-6r-in-vivo-and-a-decisive-role-of-n-glycosylation
#17
Steffen Riethmueller, Prasath Somasundaram, Johanna C Ehlers, Chien-Wen Hung, Charlotte M Flynn, Juliane Lokau, Maria Agthe, Stefan Düsterhöft, Yijue Zhu, Joachim Grötzinger, Inken Lorenzen, Tomas Koudelka, Kosuke Yamamoto, Ute Pickhinke, Rielana Wichert, Christoph Becker-Pauly, Marisa Rädisch, Alexander Albrecht, Markus Hessefort, Dominik Stahnke, Carlo Unverzagt, Stefan Rose-John, Andreas Tholey, Christoph Garbers
Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for the proinflammatory properties of IL-6 and constitutes an attractive therapeutic target, but how the sIL-6R is generated in vivo remains largely unclear. Here, we use liquid chromatography-mass spectrometry to identify an sIL-6R form in human serum that originates from proteolytic cleavage, map its cleavage site between Pro-355 and Val-356, and determine the occupancy of all O- and N-glycosylation sites of the human sIL-6R...
January 2017: PLoS Biology
https://www.readbyqxmd.com/read/28059830/2-deoxy-d-glucose-suppresses-the-migration-and-reverses-the-drug-resistance-of-colon-cancer-cells-through-adam-expression-regulation
#18
Ga B Park, Yoon H Chung, Daejin Kim
Cancer cell resistance to chemotherapy is associated with a poor prognosis. The compound 2-deoxy-D-glucose (2-DG) enhances the effect of chemotherapy against cancer cells lines in vitro and in vivo. However, its effect on the epithelial to mesenchymal transition (EMT) in drug-resistant cancer cells has not been fully elucidated. In this study, we investigated whether treatment of 5-fluorouracil or oxaliplatin-resistant colorectal cancer (CRC) cells with 2-DG suppressed their migratory activity and enhanced their susceptibility to chemotherapy...
April 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28056193/reduced-cd62l-expression-on-t-cells-and-increased-soluble-cd62l-levels-predict-molecular-response-to-tyrosine-kinase-inhibitor-therapy-in-early-chronic-phase-chronic-myelogenous-leukemia
#19
Sieghart Sopper, Satu Mustjoki, Deborah White, Timothy Hughes, Peter Valent, Andreas Burchert, Bjørn T Gjertsen, Günther Gastl, Matthias Baldauf, Zlatko Trajanoski, Frank Giles, Andreas Hochhaus, Thomas Ernst, Thomas Schenk, Jeroen J W M Janssen, Gert J Ossenkoppele, Kimmo Porkka, Dominik Wolf
Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry-based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts...
January 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28053235/inactivation-of-rab11a-gtpase-in-macrophages-facilitates-phagocytosis-of-apoptotic-neutrophils
#20
Chunling Jiang, Zheng Liu, Rong Hu, Lulong Bo, Richard D Minshall, Asrar B Malik, Guochang Hu
The timely and efficient clearance of apoptotic neutrophils by macrophages (efferocytosis) is required for the resolution of inflammation and tissue repair, but the regulatory mechanisms remain unclear. In this study, we investigated the role of the small GTPase Ras-related protein in brain (Rab)11a in regulating efferocytosis, and on this basis the resolution of inflammatory lung injury. We observed that apoptotic neutrophil feeding induced a rapid loss of Rab11a activity in bone marrow-derived macrophages and found that depletion of Rab11a in macrophages by small interfering RNA dramatically increased the phagocytosis of apoptotic neutrophils compared with control cells...
February 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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