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https://www.readbyqxmd.com/read/29777593/degradation-of-recombinant-proteins-by-cho-host-cell-proteases-is-prevented-by-matriptase-1-knock-out
#1
Holger Laux, Sandrine Romand, Sandro Nuciforo, Christopher J Farady, Joel Tapparel, Stine Buechmann-Moeller, Benjamin Sommer, Edward J Oakeley, Ursula Bodendorf
An increasing number of non-antibody format proteins are entering the clinical development. However, one of the major hurdles for the production of non-antibody glycoproteins is host cell-related proteolytic degradation, which can drastically impact developability and timelines of pipeline projects. Chinese hamster ovary (CHO) cells are the preferred production host for recombinant therapeutic proteins. Using protease inhibitors, transcriptomics and genetic knockdowns we have identified, out of the more than 700 known proteases in rodents, Matriptase-1 as the major protease involved in degradation of recombinant proteins expressed in CHO-K1 cells...
May 19, 2018: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/29769007/qsar-and-docking-studies-on-piperidyl-cyclohexylurea-derivatives-for-prediction-of-selective-and-potent-inhibitor-of-matriptase
#2
Agha Zeeshan Mirza, Hina Shamshad
QSAR models as PLS, GFA, and 3D were developed for series of matriptase inhibitors using 35 piperidyl-cyclohexylurea compounds. The training and test sets were divided into a set of 28 and 8 compounds, respectively and the pki values of each compound were used in the analysis. Docking and alignment methodologies were used to develop models in 3D QSAR. The best models among all were selected on the basis of regression statistics as r2, predictive r2 and Friedman Lack of fit measure. Hydrogen donors and rotatable bonds were found to be positively correlated properties for this target...
May 16, 2018: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/29611532/a-disease-causing-novel-missense-mutation-in-the-st14-gene-underlies-autosomal-recessive-ichthyosis-with-hypotrichosis-syndrome-in-a-consanguineous-family
#3
Farooq Ahmad, Ishtaiq Ahmed, Abdul Nasir, Muhammad Umair, Shaheen Shahzad, Dost Muhammad, Regie Lyn P Santos-Cortez, Suzanne M Leal, Wasim Ahmad
Autosomal recessive ichthyosis with hypotrichosis (ARIH; MIM 602400) syndrome is characterized by diffused congenital ichthyosis and generalized non-scarring hypotrichosis. The underlying genetic cause of ARIH syndrome has been associated with sequence variants of the gene ST14, encoding type II transmembrane serine protease matriptase, which maps to chromosome 11q24.3. The current report aimed to investigate the clinical features and genetic cause of ARIH syndrome in a large consanguineous family of Pakistani origin...
March 27, 2018: European Journal of Dermatology: EJD
https://www.readbyqxmd.com/read/29560101/regulation-of-matriptase-and-hai-1-system-a-novel-therapeutic-target-in-human-endometrial-cancer-cells
#4
Pengming Sun, Lifang Xue, Yiyi Song, Xiaodan Mao, Lili Chen, Binhua Dong, Elena Loana Braicu, Jalid Sehouli
The effects of specific and non-specific regulation of matriptase on endometrial cancer cells in vitro were investigated. Messenger ribonucleic acid (mRNA) and protein expression of matriptase and hepatocyte growth factor activator inhibitor-1 (HAI-1) in RL-952, HEC-1A, and HEC-1B endometrial cancer cells were detected by real-time quantitative PCR (RT-qPCR) and western blot. The cells were infected with lentivirus-mediated small-interfering RNA (siRNA) targeted on matriptase (MA-siRNA) or treated with different cisplatin (DDP) concentrations...
February 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29545930/hepatocyte-growth-factor-activator-inhibitor-type-2-hai-2-spint2-contributes-to-invasive-growth-of-oral-squamous-cell-carcinoma-cells
#5
Koji Yamamoto, Makiko Kawaguchi, Takeshi Shimomura, Aya Izumi, Kazuomi Konari, Arata Honda, Chen-Yong Lin, Michael D Johnson, Yoshihiro Yamashita, Tsuyoshi Fukushima, Hiroaki Kataoka
Hepatocyte growth factor activator inhibitor (HAI)-1/ SPINT1 and HAI-2/ SPINT2 are membrane-anchored protease inhibitors having homologous Kunitz-type inhibitor domains. They regulate membrane-anchored serine proteases, such as matriptase and prostasin. Whereas HAI-1 suppresses the neoplastic progression of keratinocytes to invasive squamous cell carcinoma (SCC) through matriptase inhibition, the role of HAI-2 in keratinocytes is poorly understood. In vitro homozygous knockout of the SPINT2 gene suppressed the proliferation of two oral SCC (OSCC) lines (SAS and HSC3) but not the growth of a non-tumorigenic keratinocyte line (HaCaT)...
February 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29532159/expression-of-serine-peptidase-inhibitor-kunitz-type-1-in-differentiated-thyroid-cancer
#6
Chien-Liang Liu, Po-Sheng Yang, Ming-Nan Chien, Yuan-Ching Chang, Chi-Hsin Lin, Shih-Ping Cheng
SPINT1, also known as HAI-1, is a Kunitz-type serine protease inhibitor that inhibits multiple proteases including hepatocyte growth factor (HGF) activator and matriptase. SPINT1 has been shown to modulate HGF/MET activation in certain cancer types. In the present study, we analyzed microarray datasets and found that SPINT1 was consistently upregulated in differentiated thyroid cancer. SPINT1 protein expression was investigated using tissue microarrays and independent samples of our 143 patients. Strong SPINT1 expression was observed in 61-68% of papillary thyroid cancer and 41-50% of follicular thyroid cancer...
March 12, 2018: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/29518524/the-impaired-proteases-and-anti-proteases-balance-in-idiopathic-pulmonary-fibrosis
#7
REVIEW
Awen Menou, JanWillem Duitman, Bruno Crestani
Idiopathic Pulmonary Fibrosis (IPF) is a devastating chronic, progressive and irreversible disease that remains refractory to current therapies. Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the development of pulmonary fibrosis since decades. Coagulation signalling deregulation, which influences several key inflammatory and fibro-proliferative responses, is also essential in IPF pathogenesis, and a growing body of evidence indicates that Protease-Activated Receptors (PARs) inhibition in IPF may be promising for future evaluation...
March 6, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/29509988/capsaicin-induces-atopic-dermatitis-like-manifestations-through-dysregulation-of-proteolytic-system-and-alteration-of-filaggrin-processing-in-rats
#8
Sewon Kim, Seung Keun Back, Heung Sik Na, Sun-Ho Kee
Atopic dermatitis (AD) is a complex disease featuring pruritic skin inflammation. Many animal models have been developed. In a rat model, subcutaneous capsaicin injection within 48 hours after birth induces AD-like skin manifestations of dermatitis and scratching behaviour 3 weeks after the injection. When 2- to 4-week-old rats were injected with capsaicin, the lag period was shortened, and the severity of skin manifestations was significantly reduced, suggesting influences of postnatal development. Lgr6 is an epidermal stem cell marker that is normally restricted to the isthmus area of hair follicles at postnatal 2 weeks...
April 2018: Experimental Dermatology
https://www.readbyqxmd.com/read/29441715/transcriptome-analysis-reveals-tmprss6-isoforms-with-distinct-functionalities
#9
Sébastien P Dion, François Béliveau, Antoine Désilets, Mariana Gabriela Ghinet, Richard Leduc
TMPRSS6 (matriptase-2) is a type II transmembrane serine protease involved in iron homoeostasis. At the cell surface of hepatocytes, TMPRSS6 cleaves haemojuvelin (HJV) and regulates the BMP/SMAD signalling pathway leading to production of hepcidin, a key regulator of iron absorption. Although four TMPRSS6 human isoforms and three mice Tmprss6 isoforms are annotated in databases (Ensembl and RefSeq), their relative expression or activity has not been studied. Analyses of RNA-seq data and RT-PCR from human tissues reveal that TMPRSS6 isoform 1 (TMPRSS6-1) and 3 are mostly expressed in human testis while TMPRSS6-2 and TMPRSS6-4 are the main transcripts expressed in human liver, testis and pituitary...
April 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29438412/tissue-distribution-and-subcellular-localizations-determine-in-vivo-functional-relationship-among-prostasin-matriptase-hai-1-and-hai-2-in-human-skin
#10
Shiao-Pieng Lee, Chen-Yu Kao, Shun-Cheng Chang, Yi-Lin Chiu, Yen-Ju Chen, Ming-Hsing G Chen, Chun-Chia Chang, Yu-Wen Lin, Chien-Ping Chiang, Jehng-Kang Wang, Chen-Yong Lin, Michael D Johnson
The membrane-bound serine proteases prostasin and matriptase and the Kunitz-type protease inhibitors HAI-1 and HAI-2 are all expressed in human skin and may form a tightly regulated proteolysis network, contributing to skin pathophysiology. Evidence from other systems, however, suggests that the relationship between matriptase and prostasin and between the proteases and the inhibitors can be context-dependent. In this study the in vivo zymogen activation and protease inhibition status of matriptase and prostasin were investigated in the human skin...
2018: PloS One
https://www.readbyqxmd.com/read/29386351/engineering-a-potent-inhibitor-of-matriptase-from-the-natural-hepatocyte-growth-factor-activator-inhibitor-type-1-hai-1-protein
#11
Aaron C Mitchell, Deepti Kannan, Sean A Hunter, R Andres Parra Sperberg, Cheryl H Chang, Jennifer R Cochran
Dysregulated matriptase activity has been established as a key contributor to cancer progression through its activation of growth factors, including the hepatocyte growth factor (HGF). Despite its critical role and prevalence in many human cancers, limitations to developing an effective matriptase inhibitor include weak binding affinity, poor selectivity, and short circulating half-life. We applied rational and combinatorial approaches to engineer a potent inhibitor based on the hepatocyte growth factor activator inhibitor type-1 (HAI-1), a natural matriptase inhibitor...
April 6, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29328476/effect-of-a-synthetic-inhibitor-of-urokinase-plasminogen-activator-on-the-migration-and-invasion-of-human-cervical-cancer-cells-in-vitro
#12
Xuechun Wang, Zhongqing Jiang, Jian An, Xiaodan Mao, Fen Lin, Pengming Sun
As a notable feature of malignant tumors, invasion and metastasis are important events in the process of tumor progression. Amiloride, a synthetic inhibitor of urokinase plasminogen activator (uPA), is involved in these events. To evaluate the therapeutic value of amiloride in cervical cancer, HeLa cells were used as in vitro cellular models. The migration and invasion abilities of HeLa cells, in addition to the mRNA expression of matriptase, uPA, uPA receptor and 72 kDa type IV collagenase (MMP‑2), were detected using scratch assays, Transwell chamber assays and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR)...
March 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29301867/protease-signaling-regulates-apical-cell-extrusion-cell-contacts-and-proliferation-in-epithelia
#13
Antonino Schepis, Adrian Barker, Yoga Srinivasan, Eaman Balouch, Yaowu Zheng, Ian Lam, Hilary Clay, Chung-Der Hsiao, Shaun R Coughlin
Mechanisms that sense and regulate epithelial morphogenesis, integrity, and homeostasis are incompletely understood. Protease-activated receptor 2 (Par2), the Par2-activating membrane-tethered protease matriptase, and its inhibitor, hepatocyte activator inhibitor 1 (Hai1), are coexpressed in most epithelia and may make up a local signaling system that regulates epithelial behavior. We explored the role of Par2b in matriptase-dependent skin abnormalities in Hai1a-deficient zebrafish embryos. We show an unexpected role for Par2b in regulation of epithelial apical cell extrusion, roles in regulating proliferation that were opposite in distinct but adjacent epithelial monolayers, and roles in regulating cell-cell junctions, mobility, survival, and expression of genes involved in tissue remodeling and inflammation...
March 5, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29246902/identification-of-the-integrin-binding-site-on-coagulation-factor-viia-required-for-proangiogenic-par2-signaling
#14
Andrea S Rothmeier, Enbo Liu, Sagarika Chakrabarty, Jennifer Disse, Barbara M Mueller, Henrik Østergaard, Wolfram Ruf
The tissue factor (TF) pathway serves both hemostasis and cell signaling, but how cells control these divergent functions of TF remains incompletely understood. TF is the receptor and scaffold of coagulation proteases cleaving protease-activated receptor 2 (PAR2) that plays pivotal roles in angiogenesis and tumor development. Here we demonstrate that coagulation factor VIIa (FVIIa) elicits TF cytoplasmic domain-dependent proangiogenic cell signaling independent of the alternative PAR2 activator matriptase. We identify a Lys-Gly-Glu (KGE) integrin-binding motif in the FVIIa protease domain that is required for association of the TF-FVIIa complex with the active conformer of integrin β1...
February 8, 2018: Blood
https://www.readbyqxmd.com/read/29208051/a-novel-mutation-in-st14-at-a-functionally-significant-amino-acid-residue-expands-the-spectrum-of-ichthyosis-hypotrichosis-syndrome
#15
Leila Youssefian, Andrew Touati, Amir Hossein Saeidian, Omid Zargari, Sirous Zeinali, Hassan Vahidnezhad, Jouni Uitto
BACKGROUND: Mutations in the ST14 gene, encoding the serine protease matriptase, have been associated with ichthyosis-hypotrichosis syndrome (IHS), a Mendelian disorder with skin and hair manifestations which include, in addition to ichthyosis and hypotrichosis, hypohidrosis and follicular atrophoderma. However, the understanding of the specific consequences of mutations in ST14 on the development of this syndrome is incomplete. RESULTS: Using a targeted next-generation sequencing array of 38 ichthyosis-associated genes on a large cohort of 180 ichthyosis patients from a primarily consanguineous background, a previously unreported homozygous p...
December 6, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29196708/the-serine-proteinase-hepsin-is-an-activator-of-pro-matrix-metalloproteinases-molecular-mechanisms-and-implications-for-extracellular-matrix-turnover
#16
David J Wilkinson, Antoine Desilets, Hua Lin, Sarah Charlton, Maria Del Carmen Arques, Adrian Falconer, Craig Bullock, Yu-Chen Hsu, Kristian Birchall, Alastair Hawkins, Paul Thompson, William R Ferrell, John Lockhart, Robin Plevin, Yadan Zhang, Emma Blain, Shu-Wha Lin, Richard Leduc, Jennifer M Milner, Andrew D Rowan
Increasing evidence implicates serine proteinases in the proteolytic cascades leading to the pathological destruction of extracellular matrices such as cartilage in osteoarthritis (OA). We have previously demonstrated that the type II transmembrane serine proteinase (TTSP) matriptase acts as a novel initiator of cartilage destruction via the induction and activation of matrix metalloproteinases (MMPs). Hepsin is another TTSP expressed in OA cartilage such that we hypothesized this proteinase may also contribute to matrix turnover...
December 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29136618/hepcidin-in-iron-homeostasis-diagnostic-and-therapeutic-implications-in-type-2-diabetes-mellitus-patients
#17
Sintayehu Ambachew, Belete Biadgo
The prevalence of type 2 diabetes is increasing in epidemic proportions worldwide. Evidence suggests body iron overload is frequently linked and observed in patients with type 2 diabetes. Body iron metabolism is based on iron conservation and recycling by which only a part of the daily need is replaced by duodenal absorption. The principal liver-produced peptide called hepcidin plays a fundamental role in iron metabolism. It directly binds to ferroportin, the sole iron exporter, resulting in the internalization and degradation of ferroportin...
2017: Acta Haematologica
https://www.readbyqxmd.com/read/29125730/development-of-a-protease-biosensor-based-on-a-dimerization-dependent-red-fluorescent-protein
#18
Aaron C Mitchell, Spencer C Alford, Sean A Hunter, Deepti Kannan, R Andres Parra Sperberg, Cheryl H Chang, Jennifer R Cochran
Dysregulated activity of the protease matriptase is a key contributor to aggressive tumor growth, cancer metastasis, osteoarthritis, and iron overload disease. Methods for the detection and quantification of matriptase activity and inhibition would be useful tools. To address this need, we developed a matriptase-sensitive protein biosensor based on a dimerization-dependent red fluorescent protein (ddRFP) reporter system. In this platform, two adjoining protein domains, connected by a protease-labile linker, produce fluorescence when assembled and are non-fluorescent when the linker is cleaved by matriptase...
November 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29118397/the-kunitz-domain-i-of-hepatocyte-growth-factor-activator-inhibitor-2-inhibits-matriptase-activity-and-invasive-ability-of-human-prostate-cancer-cells
#19
Shang-Ru Wu, Chen-Hsin Teng, Ya-Ting Tu, Chun-Jung Ko, Tai-Shan Cheng, Shao-Wei Lan, Hsin-Ying Lin, Hsin-Hsien Lin, Hsin-Fang Tu, Pei-Wen Hsiao, Hsiang-Po Huang, Chung-Hsin Chen, Ming-Shyue Lee
Dysregulation of pericellular proteolysis is often required for tumor invasion and cancer progression. It has been shown that down-regulation of hepatocyte growth factor activator inhibitor-2 (HAI-2) results in activation of matriptase (a membrane-anchored serine protease), human prostate cancer cell motility and tumor growth. In this study, we further characterized if HAI-2 was a cognate inhibitor for matriptase and identified which Kunitz domain of HAI-2 was required for inhibiting matriptase and human prostate cancer cell motility...
November 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29054928/the-type-ii-transmembrane-serine-protease-matriptase-cleaves-the-amyloid-precursor-protein-and-reduces-its-processing-to-%C3%AE-amyloid-peptide
#20
COMPARATIVE STUDY
Erwan Lanchec, Antoine Désilets, François Béliveau, Anthony Flamier, Shaimaa Mahmoud, Gilbert Bernier, Denis Gris, Richard Leduc, Christine Lavoie
Recent studies have reported that many proteases, besides the canonical α-, β-, and γ-secretases, cleave the amyloid precursor protein (APP) and modulate β-amyloid (Aβ) peptide production. Moreover, specific APP isoforms contain Kunitz protease-inhibitory domains, which regulate the proteolytic activity of serine proteases. This prompted us to investigate the role of matriptase, a member of the type II transmembrane serine protease family, in APP processing. Using quantitative RT-PCR, we detected matriptase mRNA in several regions of the human brain with an enrichment in neurons...
December 15, 2017: Journal of Biological Chemistry
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