P4-Atpases As Phospholipid Flippases—Structure, Function, and Enigmas
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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. -
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 -
Macropinocytosis Requires Gal-3 in a Subset of Patient-Derived Glioblastoma Stem Cells
ARTICLE https://doi.org/10.1038/s42003-021-02258-z OPEN Macropinocytosis requires Gal-3 in a subset of patient-derived glioblastoma stem cells Laetitia Seguin1,8, Soline Odouard2,8, Francesca Corlazzoli 2,8, Sarah Al Haddad2, Laurine Moindrot2, Marta Calvo Tardón3, Mayra Yebra4, Alexey Koval5, Eliana Marinari2, Viviane Bes3, Alexandre Guérin 6, Mathilde Allard2, Sten Ilmjärv6, Vladimir L. Katanaev 5, Paul R. Walker3, Karl-Heinz Krause6, Valérie Dutoit2, ✉ Jann N. Sarkaria 7, Pierre-Yves Dietrich2 & Érika Cosset 2 Recently, we involved the carbohydrate-binding protein Galectin-3 (Gal-3) as a druggable target for KRAS-mutant-addicted lung and pancreatic cancers. Here, using glioblastoma patient-derived stem cells (GSCs), we identify and characterize a subset of Gal-3high glio- 1234567890():,; blastoma (GBM) tumors mainly within the mesenchymal subtype that are addicted to Gal-3- mediated macropinocytosis. Using both genetic and pharmacologic inhibition of Gal-3, we showed a significant decrease of GSC macropinocytosis activity, cell survival and invasion, in vitro and in vivo. Mechanistically, we demonstrate that Gal-3 binds to RAB10, a member of the RAS superfamily of small GTPases, and β1 integrin, which are both required for macro- pinocytosis activity and cell survival. Finally, by defining a Gal-3/macropinocytosis molecular signature, we could predict sensitivity to this dependency pathway and provide proof-of- principle for innovative therapeutic strategies to exploit this Achilles’ heel for a significant and unique subset of GBM patients. 1 University Côte d’Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging (IRCAN), Nice, France. 2 Laboratory of Tumor Immunology, Department of Oncology, Center for Translational Research in Onco-Hematology, Swiss Cancer Center Léman (SCCL), Geneva University Hospitals, University of Geneva, Geneva, Switzerland. -
Research Article Identification of ATP8B1 As a Tumor Suppressor Gene for Colorectal Cancer and Its Involvement in Phospholipid Homeostasis
Hindawi BioMed Research International Volume 2020, Article ID 2015648, 16 pages https://doi.org/10.1155/2020/2015648 Research Article Identification of ATP8B1 as a Tumor Suppressor Gene for Colorectal Cancer and Its Involvement in Phospholipid Homeostasis Li Deng,1,2 Geng-Ming Niu,1 Jun Ren,1 and Chong-Wei Ke 1 1Department of General Surgery, The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai, China 2Department of General Surgery, The Shanghai Public Health Clinical Center, Fudan University, Shanghai, China Correspondence should be addressed to Chong-Wei Ke; [email protected] Received 5 May 2020; Revised 16 July 2020; Accepted 17 August 2020; Published 29 September 2020 Academic Editor: Luis Loura Copyright © 2020 Li Deng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Homeostasis of membrane phospholipids plays an important role in cell oncogenesis and cancer progression. The flippase ATPase class I type 8b member 1 (ATP8B1), one of the P4-ATPases, translocates specific phospholipids from the exoplasmic to the cytoplasmic leaflet of membranes. ATP8B1 is critical for maintaining the epithelium membrane stability and polarity. However, the prognostic values of ATP8B1 in colorectal cancer (CRC) patients remain unclear. We analyzed transcriptomics, genomics, and clinical data of CRC samples from The Cancer Genome Atlas (TCGA). ATP8B1 was the only potential biomarker of phospholipid transporters in CRC. Its prognostic value was also validated with the data from the Gene Expression Omnibus (GEO). Compared to the normal group, the expression of ATP8B1 was downregulated in the tumor group and the CRC cell lines, which declined with disease progression. -
TITLE Biallelic Truncation Variants in ATP9A Are Associated with a Novel
medRxiv preprint doi: https://doi.org/10.1101/2021.05.31.21257832; this version posted June 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . TITLE Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder AUTHORS Francesca Mattioli1,10, Hossein Darvish2,10, Sohail Aziz Paracha3, Abbas Tafakhori4, Saghar Ghasemi Firouzabadi5, Marjan Chapi4, Hafiz Muhammad Azhar Baig6, Alexandre Reymond1,*, Stylianos E. Antonarakis7,8,*, Muhammad Ansar7,9 1Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. 2Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. 3Anatomy Department, Khyber Medical University Institute of Medical Sciences (KIMS) Kohat, Pakistan. 4Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. 5Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. 6Department of Biochemistry, Institute of Biochemistry, Biotechnology and Bioinformatics, The Islamia University of Bahawalpur, Bahawalpur, Pakistan. 7Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland. 8Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland. 9Present address: Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland. 10This authors contributed equally to this work * Corresponding authors: Alexandre Reymond, [email protected] Stylianos E. Antonarakis, [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. -
Identification of Transcriptional Mechanisms Downstream of Nf1 Gene Defeciency in Malignant Peripheral Nerve Sheath Tumors Daochun Sun Wayne State University
Wayne State University DigitalCommons@WayneState Wayne State University Dissertations 1-1-2012 Identification of transcriptional mechanisms downstream of nf1 gene defeciency in malignant peripheral nerve sheath tumors Daochun Sun Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Recommended Citation Sun, Daochun, "Identification of transcriptional mechanisms downstream of nf1 gene defeciency in malignant peripheral nerve sheath tumors" (2012). Wayne State University Dissertations. Paper 558. This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. IDENTIFICATION OF TRANSCRIPTIONAL MECHANISMS DOWNSTREAM OF NF1 GENE DEFECIENCY IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS by DAOCHUN SUN DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2012 MAJOR: MOLECULAR BIOLOGY AND GENETICS Approved by: _______________________________________ Advisor Date _______________________________________ _______________________________________ _______________________________________ © COPYRIGHT BY DAOCHUN SUN 2012 All Rights Reserved DEDICATION This work is dedicated to my parents and my wife Ze Zheng for their continuous support and understanding during the years of my education. I could not achieve my goal without them. ii ACKNOWLEDGMENTS I would like to express tremendous appreciation to my mentor, Dr. Michael Tainsky. His guidance and encouragement throughout this project made this dissertation come true. I would also like to thank my committee members, Dr. Raymond Mattingly and Dr. John Reiners Jr. for their sustained attention to this project during the monthly NF1 group meetings and committee meetings, Dr. -
ATP8B3 Blocking Peptide (N-Term) Synthetic Peptide Catalog # BP20206A
10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 ATP8B3 Blocking Peptide (N-term) Synthetic peptide Catalog # BP20206A Specification ATP8B3 Blocking Peptide (N-term) - ATP8B3 Blocking Peptide (N-term) - Product Background Information The protein encoded by this gene belongs to Primary Accession O60423 the family of Other Accession NP_620168.1 P-type cation transport ATPases, and to the subfamily of aminophospholipid-transporting ATPases. The ATP8B3 Blocking Peptide (N-term) - Additional Information aminophospholipid translocases transport phosphatidylserine and phosphatidylethanolamine from one side of a Gene ID 148229 bilayer to another. This gene encodes the member 3 of the Other Names phospholipid-transporting Phospholipid-transporting ATPase IK, ATPase 8B. Alternatively spliced transcript ATPase class I type 8B member 3, ATP8B3, variants encoding ATP1K, FOS37502_2 different isoforms have been found for this Target/Specificity gene. [provided by The synthetic peptide sequence is selected RefSeq]. from aa 71-84 of HUMAN ATP8B3 ATP8B3 Blocking Peptide (N-term) - Format References Peptides are lyophilized in a solid powder format. Peptides can be reconstituted in Scott, L.J., et al. Proc. Natl. Acad. Sci. U.S.A. solution using the appropriate buffer as 106(18):7501-7506(2009) needed. Harris, M.J., et al. Biochim. Biophys. Acta 1633(2):127-131(2003) Storage Halleck, M.S., et al. Physiol. Genomics Maintain refrigerated at 2-8°C for up to 6 1(3):139-150(1999) months. For long term storage store at Fries, A.S., et al. Lab. Anim. 12(1):1-4(1978) -20°C. Precautions This product is for research use only. -
Supplementary Table 1
Supplementary Table 1. 492 genes are unique to 0 h post-heat timepoint. The name, p-value, fold change, location and family of each gene are indicated. Genes were filtered for an absolute value log2 ration 1.5 and a significance value of p ≤ 0.05. Symbol p-value Log Gene Name Location Family Ratio ABCA13 1.87E-02 3.292 ATP-binding cassette, sub-family unknown transporter A (ABC1), member 13 ABCB1 1.93E-02 −1.819 ATP-binding cassette, sub-family Plasma transporter B (MDR/TAP), member 1 Membrane ABCC3 2.83E-02 2.016 ATP-binding cassette, sub-family Plasma transporter C (CFTR/MRP), member 3 Membrane ABHD6 7.79E-03 −2.717 abhydrolase domain containing 6 Cytoplasm enzyme ACAT1 4.10E-02 3.009 acetyl-CoA acetyltransferase 1 Cytoplasm enzyme ACBD4 2.66E-03 1.722 acyl-CoA binding domain unknown other containing 4 ACSL5 1.86E-02 −2.876 acyl-CoA synthetase long-chain Cytoplasm enzyme family member 5 ADAM23 3.33E-02 −3.008 ADAM metallopeptidase domain Plasma peptidase 23 Membrane ADAM29 5.58E-03 3.463 ADAM metallopeptidase domain Plasma peptidase 29 Membrane ADAMTS17 2.67E-04 3.051 ADAM metallopeptidase with Extracellular other thrombospondin type 1 motif, 17 Space ADCYAP1R1 1.20E-02 1.848 adenylate cyclase activating Plasma G-protein polypeptide 1 (pituitary) receptor Membrane coupled type I receptor ADH6 (includes 4.02E-02 −1.845 alcohol dehydrogenase 6 (class Cytoplasm enzyme EG:130) V) AHSA2 1.54E-04 −1.6 AHA1, activator of heat shock unknown other 90kDa protein ATPase homolog 2 (yeast) AK5 3.32E-02 1.658 adenylate kinase 5 Cytoplasm kinase AK7 -
The DNA Sequence and Comparative Analysis of Human Chromosome 20
articles The DNA sequence and comparative analysis of human chromosome 20 P. Deloukas, L. H. Matthews, J. Ashurst, J. Burton, J. G. R. Gilbert, M. Jones, G. Stavrides, J. P. Almeida, A. K. Babbage, C. L. Bagguley, J. Bailey, K. F. Barlow, K. N. Bates, L. M. Beard, D. M. Beare, O. P. Beasley, C. P. Bird, S. E. Blakey, A. M. Bridgeman, A. J. Brown, D. Buck, W. Burrill, A. P. Butler, C. Carder, N. P. Carter, J. C. Chapman, M. Clamp, G. Clark, L. N. Clark, S. Y. Clark, C. M. Clee, S. Clegg, V. E. Cobley, R. E. Collier, R. Connor, N. R. Corby, A. Coulson, G. J. Coville, R. Deadman, P. Dhami, M. Dunn, A. G. Ellington, J. A. Frankland, A. Fraser, L. French, P. Garner, D. V. Grafham, C. Grif®ths, M. N. D. Grif®ths, R. Gwilliam, R. E. Hall, S. Hammond, J. L. Harley, P. D. Heath, S. Ho, J. L. Holden, P. J. Howden, E. Huckle, A. R. Hunt, S. E. Hunt, K. Jekosch, C. M. Johnson, D. Johnson, M. P. Kay, A. M. Kimberley, A. King, A. Knights, G. K. Laird, S. Lawlor, M. H. Lehvaslaiho, M. Leversha, C. Lloyd, D. M. Lloyd, J. D. Lovell, V. L. Marsh, S. L. Martin, L. J. McConnachie, K. McLay, A. A. McMurray, S. Milne, D. Mistry, M. J. F. Moore, J. C. Mullikin, T. Nickerson, K. Oliver, A. Parker, R. Patel, T. A. V. Pearce, A. I. Peck, B. J. C. T. Phillimore, S. R. Prathalingam, R. W. Plumb, H. Ramsay, C. M. -
Trisomy 21) R
www.nature.com/scientificreports OPEN Analysis of the intracellular trafc of IgG in the context of Down syndrome (trisomy 21) R. B. Cejas, M. Tamaño‑Blanco & J. G. Blanco* Persons with Down syndrome (DS, trisomy 21) have widespread cellular protein trafcking defects. There is a paucity of data describing the intracellular transport of IgG in the context of endosomal‑ lysosomal alterations linked to trisomy 21. In this study, we analyzed the intracellular trafc of IgG mediated by the human neonatal Fc receptor (FcRn) in fbroblast cell lines with trisomy 21. Intracellular IgG trafcking studies in live cells showed that fbroblasts with trisomy 21 exhibit higher proportion of IgG in lysosomes (~ 10% increase), decreased IgG content in intracellular vesicles (~ 9% decrease), and a trend towards decreased IgG recycling (~ 55% decrease) in comparison to diploid cells. Amyloid‑beta precursor protein (APP) overexpression in diploid fbroblasts replicated the increase in IgG sorting to the degradative pathway observed in cells with trisomy 21. The impact of APP on the expression of FCGRT (alpha chain component of FcRn) was investigated by APP knock down and overexpression of the APP protein. APP knock down increased the expression of FCGRT mRNA by ~ 60% in both diploid and trisomic cells. Overexpression of APP in diploid fbroblasts and HepG2 cells resulted in a decrease in FCGRT and FcRn expression. Our results indicate that the intracellular trafc of IgG is altered in cells with trisomy 21. This study lays the foundation for future investigations into the role of FcRn in the context of DS. Down syndrome (DS, trisomy 21) is the most common survivable chromosomal aneuploidy in humans. -
Inhibin, Activin, Follistatin and FSH Serum Levels and Testicular
REPRODUCTIONRESEARCH Expression of Atp8b3 in murine testis and its characterization as a testis specific P-type ATPase Eun-Yeung Gong, Eunsook Park, Hyun Joo Lee and Keesook Lee School of Biological Sciences and Technology, Hormone Research Center, Chonnam National University, Gwangju 500-757, Republic of Korea Correspondence should be addressed to K Lee; Email: [email protected] Abstract Spermatogenesis is a complex process that produces haploid motile sperms from diploid spermatogonia through dramatic morphological and biochemical changes. P-type ATPases, which support a variety of cellular processes, have been shown to play a role in the functioning of sperm. In this study, we isolated one putative androgen-regulated gene, which is the previously reported sperm-specific aminophospholipid transporter (Atp8b3, previously known as Saplt), and explored its expression pattern in murine testis and its biochemical characteristics as a P-type ATPase. Atp8b3 is exclusively expressed in the testis and its expression is developmentally regulated during testicular development. Immunohistochemistry of the testis reveals that Atp8b3 is expressed only in germ cells, especially haploid spermatids, and the protein is localized in developing acrosomes. As expected, from its primary amino acid sequence, ATP8B3 has an ATPase activity and is phosphorylated by an ATP-producing acylphosphate intermediate, which is a signature property of the P-Type ATPases. Together, ATP8B3 may play a role in acrosome development and/or in sperm function during fertilization. Reproduction (2009) 137 345–351 Introduction the removal of testosterone by hypophysectomy or ethane dimethanesulfonate (EDS) treatment in rats leads to the Spermatogenesis is one of most complex processes of cell failure of spermatogenesis (Russell & Clermont 1977, differentiation in animals, in which diploid spermatogo- Bartlett et al. -
1 Chapter I Introduction to the Role of P4-Atpases And
CHAPTER I INTRODUCTION TO THE ROLE OF P4-ATPASES AND OXYSTEROL BINDING PROTEIN HOMOLOGUES IN PROTEIN TRANSPORT The plasma membrane and membranes of organelles compartmentalize eukaryotic cells to allow formation of specialized microenvironments in the cytosol and organelle lumens. Specific reactions including glycosylation, proteolytic cleavage and degradation take place in the organellar compartments. The functional identity of each organelle is conferred by their unique set of proteins and lipids which must be transported from common site of synthesis to multiple destinations (Owen et al., 2004). Proteins are transported between organelles of the secretory and endocytic pathways by transport vesicles. Vesicles are often identified by the cytosolic coat proteins help form them, with the best characterized examples being COPI, COPII and clathrin. Clathrin is required to bud vesicles from the trans-Golgi network (TGN), endosomes, and plasma membrane for receptor mediated endocytosis. Several years ago our lab disvoered that a budding yeast protein called Drs2 is required for budding of specific class of exocytic vesicles from the TGN (Chen et al., 1999) and clathrin coated vesicles mediating vesicle transport between the TGN and early endosomes (Liu et al., 2008b). Drs2 is a type IV P-type ATPase (P4-ATPase) and lipid flippase that helps generate membrane asymmetry in biological membranes by flipping specific lipids from one leaflet to the other. Moreover DRS2 is an essential gene at low temperature (Ripmaster et al., 1993). Yeast strains harboring a distruption of DRS2 (drs2∆) grow well from 23C to 37C, but cannot grow at temperatures below 23C. My research is focused on 1 understanding why drs2∆ cells exhibit this unusually strong cold-sensitive growth defect.