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Matriptase

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https://www.readbyqxmd.com/read/28694515/physical-binding-of-endothelial-mcam-and-neural-transmembrane-protease-matriptase-novel-cell-adhesion-in-neural-stem-cell-vascular-niche
#1
Hsiu-Hui Tung, Sheau-Ling Lee
Brain neural stem cells and transit amplifying cells in the subventricular zone (SVZ) of the lateral ventricles are in direct contact with the microvascular endothelium. The mechanisms/molecules of direct cell contact in the SVZ neurovascular niche are not fully understood. We previously showed that neural stem/progenitor (NS/P) cells induce brain endothelial signaling in direct cell contact through matriptase (MTP) on NS/P cell surface. In the present study, using pull-down and LC-MS/MS, we identified melanoma cell adhesion molecule (MCAM) the brain endothelial molecule that interacts with MTP...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28691803/development-of-an-activatable-fluorescent-probe-for-prostate-cancer-imaging
#2
Takao Yogo, Keitaro Umezawa, Mako Kamiya, Rumi Hino, Yasuteru Urano
Technology to visualize small prostate cancers is urgently needed because of the difficulty of discriminating prostate cancer from normal tissue with the naked eye, and a fluorescence imaging method would be advantageous. Here we describe the design and synthesis of a fluorogenic probe (Ac-KQLR-HMRG) that is activated by hepsin and matriptase (proteases overexpressed in prostate cancer). Ac-KQLR-HMRG exhibited significant turn-on fluorogenicity in the presence of hepsin (180-fold) and matriptase (80-fold), and allowed specific fluorescence imaging of various prostate cancer cell lines in vitro...
July 10, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28671992/signaling-pathways-induced-by-serine-proteases-to-increase-intestinal-epithelial-barrier-function
#3
Kelcie A Lahey, Natalie J Ronaghan, Judie Shang, Sébastien P Dion, Antoine Désilets, Richard Leduc, Wallace K MacNaughton
Changes in barrier function of the gastrointestinal tract are thought to contribute to the inflammatory bowel diseases Crohn's disease and ulcerative colitis. Previous work in our lab demonstrated that apical exposure of intestinal epithelial cell lines to serine proteases results in an increase in transepithelial electrical resistance (TER). However, the underlying mechanisms governing this response are unclear. We aimed to determine the requirement for proteolytic activity, epidermal growth factor receptor (EGFR) activation, and downstream intracellular signaling in initiating and maintaining enhanced barrier function following protease treatment using a canine intestinal epithelial cell line (SCBN)...
2017: PloS One
https://www.readbyqxmd.com/read/28624806/targeting-the-tumor-promoting-microenvironment-in-met-amplified-nsclc-cells-with-a-novel-inhibitor-of-pro-hgf-activation
#4
Benjamin Y Owusu, Shantasia Thomas, Phanindra Venukadasula, Zhenfu Han, James W Janetka, Robert A Galemmo, Lidija Klampfer
Targeted therapeutic agents, such as inhibitors of epithelial growth factor receptor (EGFR), have transformed the management of non-small cell lung cancer (NSCLC) patients. MET-amplified NSCLC cells display resistance to EGFR-targeting agents, but are addicted to MET signaling for survival and proliferation and are sensitive to MET inhibition. However, responsive cancer cells invariably develop resistance to MET-targeted treatment.The tumor microenvironment plays a major role in resistance to anticancer therapy...
May 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28571576/matriptase-zymogen-supports-epithelial-development-homeostasis-and-regeneration
#5
Stine Friis, Daniel Tadeo, Sylvain M Le-Gall, Henrik Jessen Jürgensen, Katiuchia Uzzun Sales, Eric Camerer, Thomas H Bugge
BACKGROUND: Matriptase is a membrane serine protease essential for epithelial development, homeostasis, and regeneration, as well as a central orchestrator of pathogenic pericellular signaling in the context of inflammatory and proliferative diseases. Matriptase is an unusual protease in that its zymogen displays measurable enzymatic activity. RESULTS: Here, we used gain and loss of function genetics to investigate the possible biological functions of zymogen matriptase...
June 1, 2017: BMC Biology
https://www.readbyqxmd.com/read/28555756/design-and-chemical-syntheses-of-potent-matriptase-2-inhibitors-based-on-trypsin-inhibitor-sfti-1-isolated-from-sunflower-seeds
#6
Agata Gitlin-Domagalska, Dawid Dębowski, Anna Łęgowska, Marit Stirnberg, Joanna Okońska, Michael Gütschow, Krzysztof Rolka
Matriptase-2 plays a pivotal role in keeping iron concentrations within a narrow physiological range in humans. The opportunity to reduce matriptase-2 proteolytic activity may open a novel possibility to treat iron overload diseases, such as hereditary hemochromatosis and thalassemia. Here, we present 23 new analogues of trypsin inhibitor SFTI-1 designed to inhibit human matriptase-2. Influence of the modifications Gly1Lys, Ile10Arg and Phe12His, as well as the introduction of Narg in P1 or P1 and P4 positions were examined...
May 27, 2017: Biopolymers
https://www.readbyqxmd.com/read/28491880/iron-refractory-iron-deficiency-anemia-in-dizygotic-twins-due-to-a-novel-tmprss6-gene-mutation-in-addition-to-polymorphisms-associated-with-high-susceptibility-to-develop-ferropenic-anemia
#7
Joana Pinto, Gustavo Nobre de Jesus, Mónica Palma Anselmo, Lúcia Gonçalves, Daniela Brás, João Madeira Lopes, João Meneses, Rui Victorino, Paula Faustino
Iron refractory iron deficiency anemia (IRIDA) is an autosomal recessive ferropenic anemia. Its hypochromic microcytic pattern is associated with low transferrin saturation, normal-high ferritin, and inappropriately high hepcidin level. This entity is caused by mutants of the TMPRSS6 gene that encodes the protein matriptase II, which influences hepcidin expression, an iron metabolism counterregulatory protein. We report two 29-year-old dizygotic female twins with ferropenic, hypochromic microcytic anemia with 20 years of evolution, refractory to oral iron therapy...
April 2017: Journal of Investigative Medicine High Impact Case Reports
https://www.readbyqxmd.com/read/28490634/inflammatory-cytokines-down-regulate-the-barrier-protective-prostasin-matriptase-proteolytic-cascade-early-in-experimental-colitis
#8
Marguerite S Buzza, Tierra A Johnson, Gregory D Conway, Erik W Martin, Subhradip Mukhopadhyay, Terez Shea-Donohue, Toni M Antalis
Compromised gastrointestinal barrier function is strongly associated with the progressive and destructive pathologies of the two main forms of irritable bowel disease (IBD), ulcerative colitis (UC), and Crohn's disease (CD). Matriptase is a membrane-anchored serine protease encoded by suppression of tumorigenicity-14 (ST14) gene, which is critical for epithelial barrier development and homeostasis. Matriptase barrier-protective activity is linked with the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin, which is a co-factor for matriptase zymogen activation...
June 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28464560/matriptase-induction-of-metalloproteinase-dependent-aggrecanolysis-in-vitro-and-in-vivo-promotion-of-osteoarthritic-cartilage-damage-by-multiple-mechanisms
#9
David J Wilkinson, Angela Habgood, Heather K Lamb, Paul Thompson, Alastair R Hawkins, Antoine Désilets, Richard Leduc, Torsten Steinmetzer, Maya Hammami, Melody S Lee, Charles S Craik, Sharon Watson, Hua Lin, Jennifer M Milner, Andrew D Rowan
OBJECTIVE: To assess the ability of matriptase, a type II transmembrane serine proteinase, to promote aggrecan loss from the cartilage of patients with osteoarthritis (OA) and to determine whether its inhibition can prevent aggrecan loss and cartilage damage in experimental OA. METHODS: Aggrecan release from human OA cartilage explants and human stem cell-derived cartilage discs was evaluated, and cartilage-conditioned media were used for Western blotting. Gene expression was analyzed by real-time polymerase chain reaction...
May 2, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28454318/expression-and-prognostic-value-of-matriptase-in-ovarian-serous-adenocarcinoma
#10
Mei Ji, Shunshuang Li, Ya Xie, Zhao Zhao, Weizhong Chang, Yue Li, Xinghan Cheng, Zhuo Wang
Previous studies have demonstrated that matriptase is involved in degradation of the extracellular matrix and angiogenesis, and is overexpressed in certain forms of epithelial cancer. The present study aimed to examine matriptase expression in ovarian serous adenocarcinoma, and to investigate its association with clinicopathological characteristics and patient prognosis. Matriptase expression was analyzed in 80 ovarian serous adenocarcinoma and 12 normal ovarian tissue samples by immunohistochemistry. All data were analyzed to evaluate the association between matriptase expression and clinicopathological parameters and overall survival...
March 2017: Oncology Letters
https://www.readbyqxmd.com/read/28454094/proteolytic-cleavages-in-the-extracellular-domain-of-receptor-tyrosine-kinases-by-membrane-associated-serine-proteases
#11
Li-Mei Chen, Karl X Chai
The epithelial extracellular membrane-associated serine proteases matriptase, hepsin, and prostasin are proteolytic modifying enzymes of the extracellular domain (ECD) of the epidermal growth factor receptor (EGFR). Matriptase also cleaves the ECD of the vascular endothelial growth factor receptor 2 (VEGFR2) and the angiopoietin receptor Tie2. In this study we tested the hypothesis that these serine proteases may cleave the ECD of additional receptor tyrosine kinases (RTKs). We co-expressed the proteases in an epithelial cell line with Her2, Her3, Her4, insulin receptor (INSR), insulin-like growth factor I receptor (IGF-1R), the platelet-derived growth factor receptors (PDGFRs) α and β, or nerve growth factor receptor A (TrkA)...
April 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28447549/a-child-with-severe-iron-deficiency-anemia-and-a-complex-tmprss6-genotype
#12
Anna Paola Capra, Elisa Ferro, Laura Cannavò, Maria Angela La Rosa, Giuseppina Zirilli
OBJECTIVES: We report a case of a 7-year-old girl with severe hypochromic microcytic anemia, who was unresponsive to classical iron supplements. We suspected IRIDA, iron-refractory iron-deficiency anemia, a genetic iron metabolism disorder, caused by TMPRSS6 variations. TMPRSS6 encodes matriptase-2, a negative regulator of hepcidin, and its pathological variants are related to normal to high levels of hepcidin. We analyzed the TMPRSS6 gene and we improved clinical management of the patient, selecting the appropriate supplementation therapy...
April 27, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28393458/increased-filaggrin-metabolizing-enzyme-activity-in-atopic-skin-a-pilot-study-using-a-canine-model-of-atopic-dermatitis
#13
Natalia Fanton, Domenico Santoro, Luisa Cornegliani, Rosanna Marsella
BACKGROUND: Filaggrin (FLG) and its metabolites are essential for skin barrier function and hydration of the stratum corneum. Alteration of the FLG metabolism could be the basis for an abnormal skin barrier in allergic dogs. OBJECTIVES: To investigate the expression and distribution of calpain-1, caspase-14, furin and matriptase, four enzymes involved in FLG metabolism, in the skin of atopic and healthy beagles. METHODS: Skin biopsies were collected from four healthy and four atopic beagles before and after allergen exposure...
April 9, 2017: Veterinary Dermatology
https://www.readbyqxmd.com/read/28371047/hai-2-stabilizes-inhibits-and-regulates-sea-cleavage-dependent-secretory-transport-of-matriptase
#14
Annika W Nonboe, Oliver Krigslund, Christoffer Soendergaard, Signe Skovbjerg, Stine Friis, Martin N Andersen, Vincent Ellis, Makiko Kawaguchi, Hiroaki Kataoka, Thomas H Bugge, Lotte K Vogel
It has recently been shown that hepatocyte growth factor activator inhibitor-2 (HAI-2) is able to suppress carcinogenesis induced by overexpression of matriptase, as well as cause regression of individual established tumors in a mouse model system. However, the role of HAI-2 is poorly understood. In this study, we describe 3 mutations in the binding loop of the HAI-2 Kunitz domain 1 (K42N, C47F and R48L) that cause a delay in the SEA domain cleavage of matriptase, leading to accumulation of non-SEA domain cleaved matriptase in the endoplasmic reticulum (ER)...
March 28, 2017: Traffic
https://www.readbyqxmd.com/read/28370501/a-fluorescent-labeled-phosphono-bisbenzguanidine-as-an-activity-based-probe-for-matriptase
#15
Daniela Häußler, Anna-Christina Schulz-Fincke, Anna-Madeleine Beckmann, Aline Keils, Erik Gilberg, Martin Mangold, Jürgen Bajorath, Marit Stirnberg, Torsten Steinmetzer, Michael Gütschow
Activity-based probes are compounds that exclusively form covalent bonds with active enzymes. They can be utilized to profile enzyme activities in vivo, to identify target enzymes and to characterize their function. The design of a new activity-based probe for matriptase, a member of the type II transmembrane serine proteases, is based on linker-connected bis-benzguanidines. An amino acid, introduced as linker, bears the coumarin fluorophore. Moreover, an incorporated phosphonate allows for a covalent interaction with the active-site serine...
March 28, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28368394/inhibition-of-cyclooxygenase-2-mediated-matriptase-activation-contributes-to-the-suppression-of-prostate-cancer-cell-motility-and-metastasis
#16
C-J Ko, S-W Lan, Y-C Lu, T-S Cheng, P-F Lai, C-H Tsai, T-W Hsu, H-Y Lin, H-Y Shyu, S-R Wu, H-H Lin, P-W Hsiao, C-H Chen, H-P Huang, M-S Lee
Chronic inflammation plays an important role in cancer development and progression. Cyclooxygenases-2 (COX-2) is a key enzyme in generating prostaglandins causing inflammation, is often found to be overexpressed in prostate cancer (PCa) and is correlated with PCa cell invasion and metastasis. We aim to investigate the molecular mechanism of how COX-2 promotes PCa cell invasion and metastasis and to evaluate the effect of COX-2 inhibitors in a selected model of PCa progression. Our results showed that the expression of COX-2 and Interleukin 1β (IL-1β) was upregulated in highly invasive PCa cells and was correlated with the activated levels of membrane-anchored serine protease matriptase...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28362108/alpha1-antitrypsin-deficient-macrophages-have-increased-matriptase-mediated-proteolytic-activity
#17
Karina Krotova, George W Marek, Rejean L Wang, George Aslanidi, Brad E Hoffman, Nazli Khodayari, Farshid N Rouhani, Mark L Brantly
Alpha1-antitrypsin (AAT) deficiency-associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels by augmentation therapy only slows disease progression; the absence of full recovery indicates a more complex process of lung destruction. Because alveolar macrophages (Mɸ) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation is called Z) compromise Mɸ function and contribute to emphysema development...
March 31, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28358853/a-peptide-based-approach-to-evaluate-the-adaptability-of-influenza-a-virus-to-humans-based-on-its-hemagglutinin-proteolytic-cleavage-site
#18
Marco R Straus, Gary R Whittaker
Cleavage activation of the hemagglutinin (HA) protein by host proteases is a crucial step in the infection process of influenza A viruses (IAV). However, IAV exists in eighteen different HA subtypes in nature and their cleavage sites vary considerably. There is uncertainty regarding which specific proteases activate a given HA in the human respiratory tract. Understanding the relationship between different HA subtypes and human-specific proteases will be valuable in assessing the pandemic potential of circulating viruses...
2017: PloS One
https://www.readbyqxmd.com/read/28294512/hfe-mutations-and-iron-in-hemodialysis-patients
#19
REVIEW
Luca Valenti, Serena Pelusi
In chronic hemodialysis patients, a disruption in iron metabolism ranging from absolute to functional deficiency, with compartmentalization of this metal into macrophages, is often observed. Chronic inflammation indeed often causes an upregulation of the iron hormone hepcidin, thereby reducing iron absorption and availability to the erythron. We systematically reviewed the literature on the role of genetic risk factors on iron metabolism in hemodialysis. In this setting, mutations in the HFE gene of hereditary hemochromatosis may confer an adaptive benefit by decreasing hepcidin release, thus improving iron availability to erythropoiesis, anemia control, and the response to erythropoiesis stimulating agents and iron itself, and reducing the side effects of these therapies...
June 2017: Hemodialysis International
https://www.readbyqxmd.com/read/28219045/modulating-the-selectivity-of-matriptase-2-inhibitors-with-unnatural-amino-acids
#20
Catherine St-Georges, Antoine Désilets, François Béliveau, Mariana Ghinet, Sébastien P Dion, Éloic Colombo, Pierre-Luc Boudreault, Rafael J Najmanovich, Richard Leduc, Éric Marsault
Matriptase-2, a type II transmembrane serine protease (TTSP), is expressed in the liver and regulates iron homeostasis via the cleavage of hemojuvelin. Matriptase-2 emerges as an attractive target for the treatment of conditions associated with iron overload, such as hemochromatosis or beta-thalassemia. Starting from the crystal structure of its closest homolog matriptase, we constructed a homology model of matriptase-2 in order to further optimize the selectivity of serine trap peptidomimetic inhibitors for matriptase-2 vs matriptase...
March 31, 2017: European Journal of Medicinal Chemistry
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