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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
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
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 5, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
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 behavior 3 weeks after the injection. When 2-4-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...
March 6, 2018: Experimental Dermatology
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...
February 14, 2018: Journal of Cellular and Molecular Medicine
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
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...
January 31, 2018: Journal of Biological Chemistry
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)...
January 9, 2018: Molecular Medicine Reports
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...
January 4, 2018: Journal of Cell Biology
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 (PAR) 2 that plays pivotal roles in angiogenesis and tumor development. Here we demonstrate that coagulation factor (F) VIIa elicits TF cytoplasmic domain-dependent pro-angiogenic 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...
December 15, 2017: Blood
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
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
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...
November 15, 2017: Acta Haematologica
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
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
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
Hiroshi Kawabata
Iron is essential for various cellular processes, but an excess of iron may cause organ damage through the production of reactive oxygen species. Therefore, the amount of iron in the body must be strictly controlled. The central regulator of systemic iron homeostasis is hepcidin, which is primarily produced in the liver. Various molecules, including HFE, transferrin receptor 2 (TFR2), and hemojuvelin (HJV), are involved in sensing systemic iron status. Hepatocytes produce hepcidin in response to excess iron and inflammatory stimuli (e...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
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...
September 8, 2017: Oncotarget
Fatma H Al-Awadhi, Lilibeth A Salvador, Brian K Law, Valerie J Paul, Hendrik Luesch
Kempopeptin C, a novel chlorinated analogue of kempopeptin B, was discovered from a marine cyanobacterium collected from Kemp Channel in Florida. The structure was elucidated using NMR spectroscopy and mass spectrometry (MS). The presence of the basic Lys residue adjacent to the N-terminus of the 3-amino-6-hydroxy-2-piperidone (Ahp) moiety contributed to its selectivity towards trypsin and related proteases. The antiproteolytic activity of kempopeptin C was evaluated against trypsin, plasmin and matriptase and found to inhibit these enzymes with IC50 values of 0...
September 16, 2017: Marine Drugs
Mastura Wahedi, Aaron M Wortham, Mark D Kleven, Ningning Zhao, Shall Jue, Caroline A Enns, An-Sheng Zhang
Systemic iron homeostasis is maintained by regulation of iron absorption in the duodenum, iron recycling from erythrocytes, and iron mobilization from the liver and is controlled by the hepatic hormone hepcidin. Hepcidin expression is induced via the bone morphogenetic protein (BMP) signaling pathway that preferentially uses two type I (ALK2 and ALK3) and two type II (ActRIIA and BMPR2) BMP receptors. Hemojuvelin (HJV), HFE, and transferrin receptor-2 (TfR2) facilitate this process presumably by forming a plasma membrane complex with BMP receptors...
November 3, 2017: Journal of Biological Chemistry
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