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https://www.readbyqxmd.com/read/27895032/molecular-pathways-receptor-ectodomain-shedding-in-treatment-resistance-and-monitoring-of-cancer
#1
Miles A Miller, Ryan J Sullivan, Douglas A Lauffenburger
Proteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently over-expressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL-6R; the Notch receptors; type-I and -III TGF-β receptors; receptor tyrosine kinases (RTKs) such as HER2, HER4, and VEGFR2; and in particular, MET and TAM-family RTKs AXL and Mer (MerTK)...
November 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27878499/therapeutic-potential-of-adam17-modulation-in-gastric-cancer-through-regulation-of-the-egfr-and-tnf-%C3%AE-signalling-pathways
#2
Jinbing Sun, Jianlong Jiang, Kuangyi Lu, Qiao Chen, Danhao Tao, Zhong Chen
A disintegrin and metalloproteinase 17 (ADAM17) is highly expressed in various tumours and affects tumour progression. In this study, ADAM17 expression in 60 gastric cancer and 20 normal gastric mucosal tissues was assessed using immunohistochemistry. ADAM17 expression was higher in gastric cancer tissues than in normal gastric mucosal tissues (P < 0.0005). A significant relationship was identified between ADAM17 expression and the depth of tumour invasion, metastasis, and carcinoma stage. Furthermore, the effects of ADAM17 knockdown on the proliferation, cell invasion, and apoptosis of human gastric carcinoma cells (SGC-7901) were determined...
November 22, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27874952/nox1-promotes-colon-cancer-cell-metastasis-via-activation-of-the-adam17-pathway
#3
H-P Wang, X Wang, L-F Gong, W-J Chen, Z Hao, S-W Feng, Y-B Wu, T Ye, Y-K Cai
OBJECTIVE: Reactive oxygen species (ROS) generated by endogenous metabolic enzymes are involved in a variety of pathology processes, including cancer. In particular, superoxide-generating NADPH oxidase 1 (Nox1), a member of Nox enzyme family, is highly expressed in the colon tissue and has been implicated in physiological and pathophysiological states of colon cancer. However, the underlying molecular mechanism of Nox1 in the regulation of colon cancer progression remains largely unknown...
November 2016: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/27869207/erratum-control-of-adam17-activity-by-regulation-of-its-cellular-localisation
#4
Inken Lorenzen, Juliane Lokau, Yvonne Korpys, Mirja Oldefest, Charlotte M Flynn, Ulrike Künzel, Christoph Garbers, Matthew Freeman, Joachim Grötzinger, Stefan Düsterhöft
No abstract text is available yet for this article.
November 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27863335/il-6-trans-signaling-is-another-pathway-to-upregulate-osteopontin
#5
Takaaki Uchibori, Kazuyuki Matsuda, Takahiro Shimodaira, Mitsutoshi Sugano, Takeshi Uehara, Takayuki Honda
BACKGROUND: Osteopontin (OPN) is a pro-fibrotic molecule upregulated by pro-inflammatory cytokines. Interleukin (IL)-6 functions downstream of IL-1β and has unique signal pathways: classic- or trans-signaling via membrane-bound IL-6R or soluble IL-6R (sIL-6R). We investigated the effect of IL-6 trans-signaling on the upregulation of OPN. METHODS: We used THP-1 cells and THP-1 macrophages differentiated from THP-1 cells using phorbol 12-myristate 13-acetate (PMA)...
November 15, 2016: Cytokine
https://www.readbyqxmd.com/read/27837433/tlr4-mediated-galectin-1-production-triggers-epithelial-mesenchymal-transition-in-colon-cancer-cells-through-adam10-and-adam17-associated-lactate-production
#6
Ga Bin Park, Daejin Kim
Toll-like receptor 4 (TLR4) activation is a key contributor to the carcinogenesis of colon cancer. Overexpression of galectin-1 (Gal-1) also correlates with increased invasive activity of colorectal cancer. Lactate production is a critical predictive factor of risk of metastasis, but the functional relationship between intracellular lactate and Gal-1 expression in TLR4-activated colon cancer remains unknown. In this study, we investigated the underlying mechanism and role of Gal-1 in metastasis and invasion of colorectal cancer (CRC) cells after TLR4 stimulation...
November 12, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27809714/the-regulation-of-sema4d-exodomain-shedding-by-protein-kinase-a-in-platelets
#7
T Chen, D Z Xu, Q Li, P Mou, Z Zeng, L F Brass, L Zhu
We have previously shown that Sema4D expressed on the platelet plasma membrane can be cleaved by the metalloprotease ADAM17, producing a 120-kDa exodomain fragment that retains biological activity and remnant fragments of 24-28 kDa that remain associated with the platelet membrane. This process is modulated by calmodulin. Here we investigated the potential role of protein kinase A (PKA) in these events. Using a pharmacological approach, we now show that inhibition of PKA by H89 is sufficient to induce Sema4D exodomain shedding, while activation of PKA inhibits agonist-initiated shedding...
November 2016: Platelets
https://www.readbyqxmd.com/read/27806985/high-fat-diet-induced-glucose-dysregulation-is-independent-of-changes-in-islet-ace2-in-mice
#8
Harshita Chodavarapu, Kavaljit H Chhabra, Huijing Xia, Vinayak Shenoy, Xinping Yue, Eric Lazartigues
While restoration of ACE2 activity in the pancreas leads to improvement of glycemia in experimental models of type 2 diabetes, global deficiency in ACE2 disrupts β-cell function and impairs glucose tolerance in mice, demonstrating the physiological role of ACE2 in glucose homeostasis. Although the contribution of pancreatic ACE2 to glucose regulation has been demonstrated in genetic models of diabetes and in models with overexpression of the renin-angiotensin system (RAS), it is unclear whether islet ACE2 is involved in glycemic control in common models of human type 2 diabetes...
November 2, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/27803674/a-disintegrin-and-metalloprotease-17-in-the-cardiovascular-and-central-nervous-systems
#9
REVIEW
Jiaxi Xu, Snigdha Mukerjee, Cristiane R A Silva-Alves, Alynne Carvalho-Galvão, Josiane C Cruz, Camille M Balarini, Valdir A Braga, Eric Lazartigues, Maria S França-Silva
ADAM17 is a metalloprotease and disintegrin that lodges in the plasmatic membrane of several cell types and is able to cleave a wide variety of cell surface proteins. It is somatically expressed in mammalian organisms and its proteolytic action influences several physiological and pathological processes. This review focuses on the structure of ADAM17, its signaling in the cardiovascular system and its participation in certain disorders involving the heart, blood vessels, and neural regulation of autonomic and cardiovascular modulation...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27790089/proteomic-substrate-identification-for-membrane-proteases-in-the-brain
#10
REVIEW
Stephan A Müller, Simone D Scilabra, Stefan F Lichtenthaler
Cell-cell communication in the brain is controlled by multiple mechanisms, including proteolysis. Membrane-bound proteases generate signaling molecules from membrane-bound precursor proteins and control the length and function of cell surface membrane proteins. These proteases belong to different families, including members of the "a disintegrin and metalloprotease" (ADAM), the beta-site amyloid precursor protein cleaving enzymes (BACE), membrane-type matrix metalloproteases (MT-MMP) and rhomboids. Some of these proteases, in particular ADAM10 and BACE1 have been shown to be essential not only for the correct development of the mammalian brain, but also for myelination and maintaining neuronal connections in the adult nervous system...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27784899/plasma-ang2-and-adam17-levels-are-elevated-during-clinical-malaria-ang2-level-correlates-with-severity-and-expression-of-epcr-binding-pfemp1
#11
Jens E V Petersen, Sixbert I Mkumbaye, Anna V Vaaben, Alphaxard Manjurano, Eric Lyimo, Reginald A Kavishe, Steven B Mwakalinga, Jacklin Mosha, Daniel T R Minja, John P A Lusingu, Thor G Theander, Thomas Lavstsen, Christian W Wang
The pathogenesis of Plasmodium falciparum malaria involves a complex interplay between parasite adhesion and inflammatory response that includes release of cytokines and activation of the endothelium with accompanying release of Angiopoitin 2 (Ang2) to the plasma. A-disintegrin and metalloproteinase 17 (ADAM17) is a protein responsible for releasing cytokines, including Tumor Necrosis Factor α (TNFα), and shedding of adhesion proteins. In this study, we show that plasma levels of ADAM17 are increased in Tanzanian children hospitalized with a malaria infection compared with asymptomatic children but similar to children hospitalized with other infectious diseases...
October 27, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27784219/serum-starvation-induces-bace1-processing-and-secretion
#12
Alexandra-Vasiliki Stavropoulou, Olga Mavrofrydi, Paul Saftig, Spiros Efthimiopoulos
β-secretase (BACE1) is a type 1 transmembrane protein implicated in Alzheimer's Disease (AD) pathogenesis. Cleavage of Amyloid Precursor Protein (APP), initiated by BACE1 and followed by γ-secretase, leads to the formation of toxic Aβ peptides. Increased levels of BACE1 have been detected in the CSF of AD patients compared to age-matched healthy controls indicating that neurodegenerative conditions induce shedding of BACE1. To mimic such conditions, we examined whether serum deprivation stimulates proteolysis-dependent secretion of BACE1...
October 25, 2016: Current Alzheimer Research
https://www.readbyqxmd.com/read/27779657/adam17-promotes-epithelial-mesenchymal-transition-via-tgf-%C3%AE-smad-pathway-in-gastric-carcinoma-cells
#13
Min Xu, Hailang Zhou, Chunli Zhang, Junbo He, Hong Wei, Meng Zhou, Ying Lu, Yaocheng Sun, Jerry Wanming Ding, Jian Zeng, Wanxin Peng, Fengyi Du, Aihua Gong
Although a disintegrin and metalloproteinase-17 (ADAM17) overexpression has been demonstrated in numerous human tumors including gastric cancer, its role in gastric cancer development remains to be clarified. In the present study, we identify that ADAM17 activates TGF-β/Smad signaling to promote epithelial-mesenchymal transition (EMT) in gastric cancer cells. We found that ADAM17 promotes proliferation, migration and invasion in gastric carcinoma cells. Subsequently, we revealed that silencing ADAM17 induces the expression of epithelial marker of E-cadherin and downregulates expression of mesenchymal markers including N-cadherin, vimentin and Snail in MGC803 and MKN45 cells, whereas ADAM17 overexpression reverses these changes in BGC823 and HGC27 cells...
October 21, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27774114/the-disintegrin-metalloproteinases-adam10-and-adam17-are-upregulated-in-cutaneous-squamous-cell-carcinomas
#14
S-T Oh, A Stark, J Reichrath
No abstract text is available yet for this article.
January 2016: Dermato-endocrinology
https://www.readbyqxmd.com/read/27773542/hiv-nef-and-notch1-dependent-endocytosis-of-adam17-induces-vesicular-tnf-secretion-in-chronic-hiv-infection
#15
Christian Ostalecki, Sebastian Wittki, Jung-Hyun Lee, Miriam M Geist, Nadine Tibroni, Thomas Harrer, Gerold Schuler, Oliver T Fackler, Andreas S Baur
Tumor necrosis factor (TNF) is a key cytokine in HIV replication and pathogenesis. For reasons that are not entirely clear, the cytokine remains upregulated despite anti-retroviral therapy (ART). Here we demonstrate that HIV Nef induces an alternative TNF secretion mechanism that remains active in chronic infection. Ingestion of Nef-containing plasma extracellular vesicles (pEV) from ART patients by primary immune cells, but also Nef expression, induced intracellular proTNF cleavage and secretion of vesicular TNF endosomes...
October 19, 2016: EBioMedicine
https://www.readbyqxmd.com/read/27738494/adam17-in-tumor-associated-leukocytes-regulates-inflammatory-mediators-and-promotes-mammary-tumor-formation
#16
Laura R Bohrer, Thomas S Chaffee, Pavlina Chuntova, Nicholas J Brady, Patrice M Witschen, Sarah E Kemp, Andrew C Nelson, Bruce Walcheck, Kathryn L Schwertfeger
The presence of inflammatory cells within the tumor microenvironment has been tightly linked to mammary tumor formation and progression. Specifically, interactions between tumor cells and infiltrating macrophages can contribute to the generation of a pro-tumorigenic microenvironment. Understanding the complex mechanisms that drive tumor cell-macrophage cross-talk will ultimately lead to the development of approaches to prevent or treat early stage breast cancers. As described here, we demonstrate that the cell surface protease a disintegrin and metalloproteinase 17 (ADAM17) is expressed by macrophages in mammary tumors and contributes to regulating the expression of pro-inflammatory mediators, including inflammatory cytokines and the inflammatory mediator cyclooxygenase-2 (Cox-2)...
July 2016: Genes & Cancer
https://www.readbyqxmd.com/read/27737494/the-molecules-in-the-corneal-basement-membrane-zone-affected-by-mustard-exposure-suggest-potential-therapies
#17
Marion K Gordon, Andrea DeSantis-Rodrigues, Rita Hahn, Peihong Zhou, Yokechen Chang, Kathy K H Svoboda, Donald R Gerecke
Mustard exposures result in epithelial-stromal separations in the cornea and epidermal-dermal separations in the skin. Large blisters often manifest in skin, while the cornea develops microblisters, and, when enough form, the epithelium sloughs. If the exposure is severe, healing can be imperfect and can result in long-term adverse consequences. For the cornea, this could manifest as recurrent corneal erosions. Since the corneal epithelial-stromal separations are in the region identified by electron microscopy as the lamina lucida, the same region affected by the blistering disease junctional epidermolysis bullosa (JEB), we postulated that the molecules that are defective in JEB would be the same ones cleaved by mustard compounds...
August 2016: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/27731361/control-of-adam17-activity-by-regulation-of-its-cellular-localisation
#18
Inken Lorenzen, Juliane Lokau, Yvonne Korpys, Mirja Oldefest, Charlotte M Flynn, Ulrike Künzel, Christoph Garbers, Matthew Freeman, Joachim Grötzinger, Stefan Düsterhöft
An important, irreversible step in many signalling pathways is the shedding of membrane-anchored proteins. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. This central role in signalling implies that ADAM17 activity has to be tightly regulated, including at the level of localisation. Most mature ADAM17 is localised intracellularly, with only a small amount at the cell surface...
October 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27725819/sustained-immune-complex-mediated-reduction-in-cd16-expression-after-vaccination-regulates-nk-cell-function
#19
Martin R Goodier, Chiara Lusa, Sam Sherratt, Ana Rodriguez-Galan, Ron Behrens, Eleanor M Riley
Cross-linking of FcγRIII (CD16) by immune complexes induces antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells, contributing to control of intracellular pathogens; this pathway can also be targeted for immunotherapy of cancerous or otherwise diseased cells. However, downregulation of CD16 expression on activated NK cells may limit or regulate this response. Here, we report sustained downregulation of CD16 expression on NK cells in vivo after intramuscular (but not intranasal) influenza vaccination...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27723561/in-silico-approaches-and-proportional-odds-model-towards-identifying-selective-adam17-inhibitors-from-anti-inflammatory-natural-molecules
#20
Pallab Kumar Borah, Sourav Chakraborty, Anupam N Jha, Sanchaita Rajkhowa, Raj Kumar Duary
ADAM metallopeptidase domain 17 (ADAM17) is an attractive target for the development of new anti-inflammatory drugs. We aimed to identify selective inhibitors of ADAM17 against matrix metalloproteinase enzymes (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, and MMP-16) which have substantial structural similarity. Target proteins were docked with 29 anti-inflammatory natural molecule ligands and a known selective inhibitor IK682. The ligands were screened based on Lipinski rules, interaction with the ADAM17 active site cavity, and then ranked using the proportional odds model multinomial logistic regression...
October 5, 2016: Journal of Molecular Graphics & Modelling
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