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Membrane Tension Buffering by Caveolae: a Role in Cancer?
Cancer and Metastasis Reviews (2020) 39:505–517 https://doi.org/10.1007/s10555-020-09899-2 Membrane tension buffering by caveolae: a role in cancer? Vibha Singh1 & Christophe Lamaze1 Published online: 30 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Caveolae are bulb-like invaginations made up of two essential structural proteins, caveolin-1 and cavins, which are abundantly present at the plasma membrane of vertebrate cells. Since their discovery more than 60 years ago, the function of caveolae has been mired in controversy. The last decade has seen the characterization of new caveolae components and regulators together with the discovery of additional cellular functions that have shed new light on these enigmatic structures. Early on, caveolae and/ or caveolin-1 have been involved in the regulation of several parameters associated with cancer progression such as cell migration, metastasis, angiogenesis, or cell growth. These studies have revealed that caveolin-1 and more recently cavin-1 have a dual role with either a negative or a positive effect on most of these parameters. The recent discovery that caveolae can act as mechanosensors has sparked an array of new studies that have addressed the mechanobiology of caveolae in various cellular functions. This review summarizes the current knowledge on caveolae and their role in cancer development through their activity in membrane tension buffering. We propose that the role of caveolae in cancer has to be revisited through their response to the mechanical forces encountered by cancer cells during tumor mass development. Keywords Caveolae . Cancer . Mechanosensing . Mechanotransdcution . Membrane tension . -
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. -
EHD2 Is a Mechanotransducer Connecting Caveolae Dynamics with Gene Transcription
EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription Satish Kailasam Mani, Cesar Valades-Cruz, Stéphanie Torrino, Wei-Wei Shen, Cedric Blouin, Satish Kailasam Mani, Christine Viaris de Lesegno, Pierre Bost, Alexandre Grassart, Darius Köster, et al. To cite this version: Satish Kailasam Mani, Cesar Valades-Cruz, Stéphanie Torrino, Wei-Wei Shen, Cedric Blouin, et al.. EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription. Journal of Cell Biology, Rockefeller University Press, 2018, 217 (12), pp.4092-4105. 10.1083/jcb.201801122. inserm- 02426440 HAL Id: inserm-02426440 https://www.hal.inserm.fr/inserm-02426440 Submitted on 2 Jan 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - NonCommercial - ShareAlike| 4.0 International License REPORT EHD2 is a mechanotransducer connecting caveolae dynamics with gene transcription Stéphanie Torrino1,2,3*, Wei‑Wei Shen1,2,3*, Cédric M. Blouin1,2,3, Satish Kailasam Mani1,2,3, Christine Viaris de Lesegno1,2,3, Pierre Bost4,5, Alexandre Grassart6, Darius Köster7, Cesar Augusto Valades‑Cruz2,3,8, Valérie Chambon2,3,8, Ludger Johannes2,3,8, Paolo Pierobon9, Vassili Soumelis4, Catherine Coirault10, Stéphane Vassilopoulos10, and Christophe Lamaze1,2,3 Caveolae are small invaginated pits that function as dynamic mechanosensors to buffer tension variations at the plasma membrane. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
I ABSTRACT KHAREL, PRAKASH, Ph.D., December 2018 Chemistry
ABSTRACT KHAREL, PRAKASH, Ph.D., December 2018 Chemistry & Biochemistry RNA OXIDATION IN MULTIPLE SCLEROSIS NEURODEGENERATION (204 PP.) Dissertation advisor: Soumitra Basu An increase in the production of reactive oxygen species (ROS) and the inability of cellular machinery to adequately neutralize the ROS thus produced, lead the cells towards oxidative stress. ROS can damage all major classes of biomolecules including proteins, DNA and RNA. Recent findings show the evidence of high level of RNA oxidation in the neuronal cells of many neurological disorders suggesting a link between RNA oxidation and neurodegeneration. We have recently discovered the presence of extensive oxidative damage in the RNA molecules of neuronal cells in postmortem brains of multiple sclerosis (MS) patients. Working on the MS model system, we have established the identity of selectively oxidized mRNA molecules under MS microenvironment in human neuronal cells. Our study reveals that many of the mRNAs linked to various neurological pathways are selectively oxidized under oxidative stress. We have demonstrated the functional consequences of mRNA oxidation in two neuropathology related mRNAs (namely Nat8l and Nlrp3 mRNA). N-acetyl aspartate transferase 8 like protein (NAT8L) is a key trans-mitochondrial membrane protein that catalyzes the transfer of acetyl group from acetyl-CoA to aspartate to form N-acetyl aspartate (NAA) and transports NAA to neuronal cytoplasm. We have discovered that the oxidation in Nat8l mRNA molecule i results in the reduced expression of NAT8L enzyme. We also observed a reduced level of NAA present in the neuronal cells under oxidative stress. Using the neuronal tissue culture and MS animal model (cuprizone mouse model), we have established that a higher mRNA oxidation results in a reduced expression of NAT8L protein, which presumably contributes to the MS disease progression by weakening the myelin production machinery. -
Cellular and Molecular Signatures in the Disease Tissue of Early
Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of -
The Expanded Endocannabinoid System/Endocannabinoidome As a Potential Target for Treating Diabetes Mellitus
Current Diabetes Reports (2019) 19:117 https://doi.org/10.1007/s11892-019-1248-9 OBESITY (KM GADDE, SECTION EDITOR) The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus Alain Veilleux1,2,3 & Vincenzo Di Marzo1,2,3,4,5 & Cristoforo Silvestri3,4,5 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease. Recent Findings As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. Summary The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D. Keywords Endocannabinoidome . Bioactive lipids . Peripheral tissues . Glucose . Insulin Introduction: The Endocannabinoid System cannabis-derived natural product, Δ9-tetrahydrocannabinol and its Subsequent Expansion (THC), responsible for most of the psychotropic, euphoric to the “Endocannabinoidome” and appetite-stimulating actions (via CB1 receptors) and immune-modulatory effects (via CB2 receptors) of marijuana, The discovery of two G protein-coupled receptors, the canna- opened the way to the identification of the endocannabinoids binoid receptor type-1 (CB1) and − 2 (CB2) [1, 2], for the (eCBs). -
Insights from Conventional and Unconventional Myosins A
Structure-Function Analysis of Motor Proteins: Insights from Conventional and Unconventional Myosins A Thesis SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY Karl J. Petersen IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Margaret A. Titus, Advisor David D. Thomas, Co-Advisor December 2016 © Karl J. Petersen 2016 Acknowledgements This thesis would not exist without the patient support of my advisors, Meg Titus and Dave Thomas. Any shortcomings are my own. Collaborators Holly Goodson, Anne Houdusse, and Gant Luxton also provided invaluable training and support. I am also grateful for essential services provided by departmental staff: Sarah Blakely Anderson, Octavian Cornea, Sarah Dittrich, Karen Hawkinson, Michelle Lewis, Mary Muwahid, Laurie O’Neill, Darlene Toedter, with apologies to others not listed. Thanks to friends and colleagues at the University of Minnesota: Ashley Arthur, Kelly Bower, Brett Colson, Sinziana Cornea, Chi Meng Fong, Greg Gillispie, Piyali Guhathakurta, Tejas Gupte, Tom Hays, Norma Jiménez Ramírez, Dawn Lowe, Allison MacLean, Santiago Martínez Cifuentes, Jared Matzke, Megan McCarthy, Joachim Mueller, Joe Muretta, Kurt Peterson, Mary Porter, Ewa Prochniewicz, Mike Ritt, Cosmo Saunders, Shiv Sivaramakrishnan, Ruth Sommese, Doug Tritschler, Brian Woolums. i Abstract Myosin motor proteins play fundamental roles in a multitude of cellular processes. Myosin generates force on cytoskeletal actin filaments to control cell shape, most dramatically during cytokinesis, and has a conserved role in defining cell polarity. Myosin contracts the actin cytoskeleton, ensuring prompt turnover of cellular adhesion sites, retracting the cell body during migration and development, and contracting muscle among diverse other functions. How myosins work, and why force generation is essential for their function, is in many cases an open question. -
Microrna Regulatory Pathways in the Control of the Actin–Myosin Cytoskeleton
cells Review MicroRNA Regulatory Pathways in the Control of the Actin–Myosin Cytoskeleton , , Karen Uray * y , Evelin Major and Beata Lontay * y Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; [email protected] * Correspondence: [email protected] (K.U.); [email protected] (B.L.); Tel.: +36-52-412345 (K.U. & B.L.) The authors contributed equally to the manuscript. y Received: 11 June 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: MicroRNAs (miRNAs) are key modulators of post-transcriptional gene regulation in a plethora of processes, including actin–myosin cytoskeleton dynamics. Recent evidence points to the widespread effects of miRNAs on actin–myosin cytoskeleton dynamics, either directly on the expression of actin and myosin genes or indirectly on the diverse signaling cascades modulating cytoskeletal arrangement. Furthermore, studies from various human models indicate that miRNAs contribute to the development of various human disorders. The potentially huge impact of miRNA-based mechanisms on cytoskeletal elements is just starting to be recognized. In this review, we summarize recent knowledge about the importance of microRNA modulation of the actin–myosin cytoskeleton affecting physiological processes, including cardiovascular function, hematopoiesis, podocyte physiology, and osteogenesis. Keywords: miRNA; actin; myosin; actin–myosin complex; Rho kinase; cancer; smooth muscle; hematopoiesis; stress fiber; gene expression; cardiovascular system; striated muscle; muscle cell differentiation; therapy 1. Introduction Actin–myosin interactions are the primary source of force generation in mammalian cells. Actin forms a cytoskeletal network and the myosin motor proteins pull actin filaments to produce contractile force. All eukaryotic cells contain an actin–myosin network inferring contractile properties to these cells. -
Globin Gene Expression in Correlation with G Protein-Related Genes During
Čokić et al. BMC Genomics 2013, 14:116 http://www.biomedcentral.com/1471-2164/14/116 RESEARCH ARTICLE Open Access Globin gene expression in correlation with G protein-related genes during erythroid differentiation Vladan P Čokić1*, Reginald D Smith2, Angélique Biancotto3, Constance T Noguchi4, Raj K Puri5 and Alan N Schechter4 Abstract Background: The guanine nucleotide binding protein (G protein)-coupled receptors (GPCRs) regulate cell growth, proliferation and differentiation. G proteins are also implicated in erythroid differentiation, and some of them are expressed principally in hematopoietic cells. GPCRs-linked NO/cGMP and p38 MAPK signaling pathways already demonstrated potency for globin gene stimulation. By analyzing erythroid progenitors, derived from hematopoietic cells through in vitro ontogeny, our study intends to determine early markers and signaling pathways of globin gene regulation and their relation to GPCR expression. Results: Human hematopoietic CD34+ progenitors are isolated from fetal liver (FL), cord blood (CB), adult bone marrow (BM), peripheral blood (PB) and G-CSF stimulated mobilized PB (mPB), and then differentiated in vitro into erythroid progenitors. We find that growth capacity is most abundant in FL- and CB-derived erythroid cells. The erythroid progenitor cells are sorted as 100% CD71+, but we did not find statistical significance in the variations of CD34, CD36 and GlyA antigens and that confirms similarity in maturation of studied ontogenic periods. During ontogeny, beta-globin gene expression reaches maximum levels in cells of adult blood origin (176 fmol/μg), while gamma-globin gene expression is consistently up-regulated in CB-derived cells (60 fmol/μg). During gamma-globin induction by hydroxycarbamide, we identify stimulated GPCRs (PTGDR, PTGER1) and GPCRs-coupled genes known to be activated via the cAMP/PKA (ADIPOQ), MAPK pathway (JUN) and NO/cGMP (PRPF18) signaling pathways. -
Synaptamide Activates the Adhesion GPCR GPR110 (ADGRF1) Through GAIN Domain Binding
ARTICLE https://doi.org/10.1038/s42003-020-0831-6 OPEN Synaptamide activates the adhesion GPCR GPR110 (ADGRF1) through GAIN domain binding Bill X. Huang1, Xin Hu2, Heung-Sun Kwon1, Cheng Fu1, Ji-Won Lee1, Noel Southall2, Juan Marugan2 & ✉ Hee-Yong Kim1 1234567890():,; Adhesion G protein-coupled receptors (aGPCR) are characterized by a large extracellular region containing a conserved GPCR-autoproteolysis-inducing (GAIN) domain. Despite their relevance to several disease conditions, we do not understand the molecular mechanism by which aGPCRs are physiologically activated. GPR110 (ADGRF1) was recently deorphanized as the functional receptor of N-docosahexaenoylethanolamine (synaptamide), a potent synap- togenic metabolite of docosahexaenoic acid. Thus far, synaptamide is the first and only small- molecule endogenous ligand of an aGPCR. Here, we demonstrate the molecular basis of synaptamide-induced activation of GPR110 in living cells. Using in-cell chemical cross-linking/ mass spectrometry, computational modeling and mutagenesis-assisted functional assays, we discover that synaptamide specifically binds to the interface of GPR110 GAIN subdomains through interactions with residues Q511, N512 and Y513, causing an intracellular conforma- tional change near TM6 that triggers downstream signaling. This ligand-induced GAIN-tar- geted activation mechanism provides a framework for understanding the physiological function of aGPCRs and therapeutic targeting in the GAIN domain. 1 Laboratory of Molecular Signaling, National Institute on Alcohol Abuse -
Lysine Methylation Regulators Moonlighting Outside the Epigenome Evan Cornett, Laure Ferry, Pierre-Antoine Defossez, Scott Rothbart
Lysine Methylation Regulators Moonlighting outside the Epigenome Evan Cornett, Laure Ferry, Pierre-Antoine Defossez, Scott Rothbart To cite this version: Evan Cornett, Laure Ferry, Pierre-Antoine Defossez, Scott Rothbart. Lysine Methylation Regulators Moonlighting outside the Epigenome. Molecular Cell, Elsevier, 2019, 10.1016/j.molcel.2019.08.026. hal-02359890 HAL Id: hal-02359890 https://hal.archives-ouvertes.fr/hal-02359890 Submitted on 14 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Lysine methylation regulators moonlighting outside the epigenome Evan M. Cornett1, Laure Ferry2, Pierre-Antoine Defossez2, and Scott B. RothBart1* 1Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. 2Université de Paris, Epigenetics and Cell Fate, CNRS, F-75013 Paris, France. *Correspondence: [email protected], 616-234-5367 ABSTRACT Landmark discoveries made nearly two decades ago identified known transcriptional regulators as histone lysine methyltransferases; since then the field of lysine methylation signaling has Been dominated By studies of how this small chemical posttranslational modification regulates gene expression and other chromatin-Based processes. However, recent advances in mass spectrometry-Based proteomics have revealed that histones are just a suBset of the thousands of eukaryotic proteins marked By lysine methylation.