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Global Analysis Reveals the Complexity of the Human Glomerular Extracellular Matrix
Global analysis reveals the complexity of the human glomerular extracellular matrix Rachel Lennon,1,2 Adam Byron,1,* Jonathan D. Humphries,1 Michael J. Randles,1,2 Alex Carisey,1 Stephanie Murphy,1,2 David Knight,3 Paul E. Brenchley,2 Roy Zent,4,5 and Martin J. Humphries.1 1Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK; 2Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; 3Biological Mass Spectrometry Core Facility, Faculty of Life Sciences, University of Manchester, Manchester, UK; 4Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; and 5Veterans Affairs Hospital, Nashville, TN, USA. *Present address: Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. Running title: Proteome of the glomerular matrix Word count: Abstract: 208, main text 2765 Corresponding author: Dr Rachel Lennon, Wellcome Trust Centre for Cell-Matrix Research, Michael Smith Building, University of Manchester, Manchester M13 9PT, UK. Phone: 0044 (0) 161 2755498. Fax: 0044 (0) 161 2755082. Email: [email protected] Abstract The glomerulus contains unique cellular and extracellular matrix (ECM) components, which are required for intact barrier function. Studies of the cellular components have helped to build understanding of glomerular disease; however, the full composition and regulation of glomerular ECM remains poorly understood. Here, we employed mass spectrometry–based proteomics of enriched ECM extracts for a global analysis of human glomerular ECM in vivo and identified a tissue-specific proteome of 144 structural and regulatory ECM proteins. This catalogue includes all previously identified glomerular components, plus many new and abundant components. -
Bruch's Membrane Abnormalities in PRDM5-Related Brittle Cornea
Porter et al. Orphanet Journal of Rare Diseases (2015) 10:145 DOI 10.1186/s13023-015-0360-4 RESEARCH Open Access Bruch’s membrane abnormalities in PRDM5-related brittle cornea syndrome Louise F. Porter1,2,3, Roberto Gallego-Pinazo4, Catherine L. Keeling5, Martyna Kamieniorz5, Nicoletta Zoppi6, Marina Colombi6, Cecilia Giunta7, Richard Bonshek2,8, Forbes D. Manson1 and Graeme C. Black1,9* Abstract Background: Brittle cornea syndrome (BCS) is a rare, generalized connective tissue disorder associated with extreme corneal thinning and a high risk of corneal rupture. Recessive mutations in transcription factors ZNF469 and PRDM5 cause BCS. Both transcription factors are suggested to act on a common pathway regulating extracellular matrix genes, particularly fibrillar collagens. We identified bilateral myopic choroidal neovascularization as the presenting feature of BCS in a 26-year-old-woman carrying a novel PRDM5 mutation (p.Glu134*). We performed immunohistochemistry of anterior and posterior segment ocular tissues, as expression of PRDM5 in the eye has not been described, or the effects of PRDM5-associated disease on the retina, particularly the extracellular matrix composition of Bruch’smembrane. Methods: Immunohistochemistry using antibodies against PRDM5, collagens type I, III, and IV was performed on the eyes of two unaffected controls and two patients (both with Δ9-14 PRDM5). Expression of collagens, integrins, tenascin and fibronectin in skin fibroblasts of a BCS patient with a novel p.Glu134* PRDM5 mutation was assessed using immunofluorescence. Results: PRDM5 is expressed in the corneal epithelium and retina. We observe reduced expression of major components of Bruch’s membrane in the eyes of two BCS patients with a PRDM5 Δ9-14 mutation. -
Defining Functional Interactions During Biogenesis of Epithelial Junctions
ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. -
Transcriptional Control of Tissue-Resident Memory T Cell Generation
Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells. -
Integrin Adhesion Molecules in the Human Endometrium. Correlation with the Normal and Abnormal Menstrual Cycle
Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle. B A Lessey, … , S M Albelda, C A Buck J Clin Invest. 1992;90(1):188-195. https://doi.org/10.1172/JCI115835. Research Article Integrins are a class of cell adhesion molecules that participate in cell-cell and cell-substratum interactions and are present on essentially all human cells. The distribution of nine different alpha and beta integrin subunits in human endometrial tissue at different stages of the menstrual cycle was determined using immunoperoxidase staining. Glandular epithelial cells expressed primarily alpha 2, alpha 3, and alpha 6 (collagen/laminin receptors), while stromal cells expressed predominantly alpha 5 (fibronectin receptor). The presence of alpha 1 on glandular epithelial cells was cycle specific, found only during the secretory phase. Expression of both subunits of the vitronectin receptor, alpha v beta 3, also underwent cycle specific changes on endometrial epithelial cells. Immunostaining for alpha v increased throughout the menstrual cycle, while the beta 3 subunit appeared abruptly on cycle day 20 on luminal as well as glandular epithelial cells. Discordant luteal phase biopsies (greater than or equal to 3 d "out of phase") from infertility patients exhibited delayed epithelial beta 3 immunostaining. These results demonstrate similarities, as well as specific differences, between endometrium and other epithelial tissues. Certain integrin moieties appear to be regulated within the cycling endometrium and disruption of integrin expression may be associated with decreased uterine receptivity and infertility. Find the latest version: https://jci.me/115835/pdf Integrin Adhesion Molecules in the Human Endometrium Correlation with the Normal and Abnormal Menstrual Cycle Bruce A. -
Supplementary Table 1: Adhesion Genes Data Set
Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like, -
Integrins: Roles in Cancer Development and As Treatment Targets
British Journal of Cancer (2004) 90, 561 – 565 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Minireview Integrins: roles in cancer development and as treatment targets 1 ,1,2 H Jin and J Varner* 1John and Rebecca Moores Comprehensive Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0912, USA; 2Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0912, USA The integrin family of cell adhesion proteins promotes the attachment and migration of cells on the surrounding extracellular matrix (ECM). Through signals transduced upon integrin ligation by ECM proteins or immunoglobulin superfamily molecules, this family of proteins plays key roles in regulating tumour growth and metastasis as well as tumour angiogenesis. Several integrins play key roles in promoting tumour angiogenesis and tumour metastasis. Antagonists of several integrins (a5b1, avb3 and avb5) are now under evaluation in clinical trials to determine their potential as therapeutics for cancer and other diseases. British Journal of Cancer (2004) 90, 561 – 565. doi:10.1038/sj.bjc.6601576 www.bjcancer.com & 2004 Cancer Research UK Keywords: angiogenesis; metastasis; apoptosis; integrin a5b1; integrin avb3 During the last 10 years, novel insights into the mechanisms sequences (e.g., integrin a4b1 recognises EILDV and REDV in that regulate cell survival as well as cell migration and invasion alternatively spliced CS-1 fibronectin). Inhibitors of integrin have led to the development of novel integrin-based therapeutics function include function-blocking monoclonal antibodies, pep- for the treatment of cancer. Several integrins play important tide antagonists and small molecule peptide mimetics matrix roles in promoting cell proliferation, migration and survival (reviewed in Hynes, 1992; Cheresh, 1993). -
The Dynamic Interaction Between Extracellular Matrix Remodeling and Breast Tumor Progression
cells Review The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression Jorge Martinez 1,* and Patricio C. Smith 2,* 1 Cell Biology Laboratory, INTA, University of Chile, Santiago 7810000, Chile 2 School of Dentistry, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile * Correspondence: [email protected] (J.M.); [email protected] (P.C.S.); Tel.: + 56-2-2987-1419 (J.M.); +56-2-2354-8400 (P.C.S.) Abstract: Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors. -
A Missense Mutation in the RSRSP Stretch of Rbm20 Causes Dilated
www.nature.com/scientificreports OPEN A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fbrillation in mice Kensuke Ihara1,2*, Tetsuo Sasano2, Yuichi Hiraoka3, Marina Togo‑Ohno4, Yurie Soejima5, Motoji Sawabe5, Megumi Tsuchiya6, Hidesato Ogawa6, Tetsushi Furukawa1 & Hidehito Kuroyanagi4* Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identifed causative mutations in over 60 genes, including RBM20, which encodes a regulator of heart‑specifc splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fbrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame‑shifting deletion demonstrated less severe phenotypes, although loss of RBM20‑dependent alternative splicing was indistinguishable. RBM20S637A protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule‑like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes. Dilated cardiomyopathy (DCM) is a fatal cardiac disease characterized by enlargement of the cardiac chambers and impaired systolic function1. -
Blood Vitronectin Is a Major Activator of LIF and IL-6 in the Brain Through Integrin–FAK and Upar Signaling Matthew P
© 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs202580. doi:10.1242/jcs.202580 RESEARCH ARTICLE Blood vitronectin is a major activator of LIF and IL-6 in the brain through integrin–FAK and uPAR signaling Matthew P. Keasey1, Cuihong Jia1, Lylyan F. Pimentel1,2, Richard R. Sante1, Chiharu Lovins1 and Theo Hagg1,* ABSTRACT Microglia and astrocytes express the VTN receptors αvβ3 and α β We defined how blood-derived vitronectin (VTN) rapidly and potently v 5 integrin (Herrera-Molina et al., 2012; Kang et al., 2008; activates leukemia inhibitory factor (LIF) and pro-inflammatory Milner, 2009; Welser-Alves et al., 2011). Microglia and astrocytes, interleukin 6 (IL-6) in vitro and after vascular injury in the brain. as well as endothelial cells, are major producers of pro- α in vitro Treatment with VTN (but not fibrinogen, fibronectin, laminin-111 or inflammatory cytokines, such as IL-6 and TNF , and collagen-I) substantially increased LIF and IL-6 within 4 h in after traumatic or ischemic injury to the brain (Banner et al., 1997; C6-astroglioma cells, while VTN−/− mouse plasma was less effective Erta et al., 2012; Lau and Yu, 2001) or upon self-induction by IL-6 than that from wild-type mice. LIF and IL-6 were induced by (Van Wagoner and Benveniste, 1999). IL-6 is a major regulator of a intracerebral injection of recombinant human (rh)VTN in mice, but variety of inflammatory disorders and a target for therapies (Hunter induction seen upon intracerebral hemorrhage was less in VTN−/− and Jones, 2015). -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations
Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations by Jelena Perovanovic M.S. in Molecular Biology and Physiology, September 2009, University of Belgrade M.Phil. in Molecular Medicine, August 2013, The George Washington University A Dissertation submitted to The Faculty of The Columbian College of Arts and Sciences of The George Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 31, 2015 Dissertation directed by Eric P. Hoffman Professor of Integrative Systems Biology The Columbian College of Arts and Sciences of The George Washington University certifies that Jelena Perovanovic has passed the Final Examination for the degree of Doctor of Philosophy as of May 5, 2015. This is the final and approved form of the dissertation. Nuclear Envelope Laminopathies: Evidence for Developmentally Inappropriate Nuclear Envelope-Chromatin Associations Jelena Perovanovic Dissertation Research Committee: Eric P. Hoffman, Professor of Integrative Systems Biology, Dissertation Director Anamaris Colberg-Poley, Professor of Integrative Systems Biology, Committee Member Robert J. Freishtat, Associate Professor of Pediatrics, Committee Member Vittorio Sartorelli, Senior Investigator, National Institutes of Health, Committee Member ii © Copyright 2015 by Jelena Perovanovic All rights reserved iii Acknowledgments I am deeply indebted to countless individuals for their support and encouragement during the past five years of graduate studies. First and foremost, I would like to express my gratitude to my mentor, Dr. Eric P. Hoffman, for his unwavering support and guidance, and keen attention to my professional development. This Dissertation would not have been possible without the critical input he provided and the engaging environment he created.