DOCSLIB.ORG

1 Background

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1 Background ! "# $ # # % & '( )!&!* &!+",& *%* +!-).!%*%! /*&!)+! //*&* 00 Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) in Medical Cell Biology presented at Uppsala University in 2002. ABSTRACT Lindholm, C. K. 2002. Shb and Its Homologues: Signaling in T Lymphocytes and Fibroblasts. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1129. 53 pp. Uppsala. ISBN 91-554-5260-4. Stimulation of the T cell receptor (TCR) induces tyrosine phosphorylation of numerous intracellular proteins, leading to activation of the interleukin-2 (IL-2) gene in T lymphocytes. Shb is a ubiquitously expressed adapter protein, with the ability to associate with the T cell receptor and several signaling proteins in T cells, including: the TCR ζ-chain, LAT, PLC-γ1, Vav, SLP-76 and Gads. Jurkat T cells expressing Shb with a mutation in the SH2 domain, exhibited reduced phosphorylation of several proteins and abolished activation of the MAP kinases ERK1, ERK2 and JNK, upon CD3 stimulation. The TCR induced Ca2+ response in these cells was abolished, together with the activation of the IL-2 promoter via the transcription factor NFAT. Consequently, IL-2 production was also perturbed in these cells, compared to normal Jurkat T cells. Shb was also seen to associate with the β and γ chains of the IL-2 receptor, upon IL-2 stimulation, in T and NK cells. This association occurred between the Shb SH2 domain and Tyr-510 of the IL-2R β chain. The proline-rich domains of Shb were found to associate with the tyrosine kinases JAK1 and JAK3, which are important for STAT-mediated proliferation of T and NK cells upon IL-2 stimulation. Shb was also found to be involved in IL-2 mediated regulation of apoptosis. These findings indicate a dual role for Shb in T cells, where Shb is involved in both T cell receptor and IL-2 receptor signaling. A Shb homologue, Shf was identified, and seen to associate with the PDGF-α-receptor. Shf shares high sequence homology with Shb and a Shd (also of the Shb family) in the SH2 domain and in four motifs containing putative tyrosine phosphorylation sites. When Shf was overexpressed in fibroblasts, these cells displayed significantly lower rates of apoptosis than control cells in the presence of PDGF-AA. These findings suggest a role for the novel adapter Shf in PDGF-receptor signaling and regulation of apoptosis. Key Words: Shb, T cell receptor, IL-2 receptor, PDGF receptor, cell signaling, adapter proteins, LAT, Vav, PLC- γ1, SLP-76, JAK1, JAK3, Jurkat cells, T cells, NK cells, Apoptosis. Cecilia K. Lindholm, Department of Medical Cell Biology, Biomedicum, Uppsala University, Box 571, S-75123 Uppsala, Sweden. Cecilia K Lindholm 2002 ISSN 0282-7476 ISBN 91-554-5260-4 Printed in Sweden by Uppsala University, Tryck & Medier, Uppsala 2002 2 To my family De spår jag kommer att avsätta blir inte som en elefants. De kanske blir som en liten nalles. Okej. Klaus Rifbjerg, Vaxdukshjärtat 3 REPORTS CONSTITUTING THE THESIS (Referred to in the text by their Roman numerals) I Cecilia K Lindholm, Erik Gylfe, Weiguo Zhang, Lawrence E Samelson and Michael Welsh (1999) Requirement of the Src Homology 2 Domain Protein Shb for T Cell Receptor-dependent Activation of the Interleukin-2 Gene Nuclear Factor for Activation of T cells Element in Jurkat T Cells. J. Biol. Chem. 274(39) 28050-28057. II Cecilia K. Lindholm, Maria L. Henriksson, Bengt Hallberg and Michael Welsh (2002) Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells. Submitted III Cecilia K. Lindholm (2002) IL-2 receptor signaling through the Shb adapter protein in T and NK cells. Manuscript IV Cecilia K. Lindholm, J. Daniel Frantz, Steven E. Shoelson and Michael Welsh (2000) Shf, a Shb-like Adapter Protein, Is Involved in PDGF-α-receptor Regulation of Apoptosis. Biochem. Biophys. Res. Comm. 278, 537-543. 4 TABLE OF CONTENTS: ABSTRACT 2 REPORTS CONSTITUTING THE THESIS 4 ABBREVIATIONS 6 INTRODUCTION AND AIMS 7 1. BACKGROUND 9 1.1. Receptors and their ligands 9 1.2. Tyrosine kinase receptors 9 1.3. Hematopoietic receptors 9 1.4. Cytokine receptors 10 1.5. Protein kinases 11 1.6. Adapter proteins 13 1.7. Monomeric G proteins and Guanine nucleotide exchange factors 16 1.8. Phospholipases 17 1.9. The Shb adapter protein 18 1.10. The Shd and She adapter proteins 20 1.11. Subcellular localization 21 1.12. Gene activation 21 1.13. Cell survival and cell death 22 2. METHODOLOGY 24 2.1. DNA 24 2.2. RNA 25 2.3. Proteins 25 2.4. Protein-protein interactions 26 2.5. Cellular processes 27 3. RESULTS AND DISCUSSION 31 3.1. A role for Shb in the early events of TCR signaling. 31 3.2. Effects of overexpression of Shb, with a defect SH2 domain, in Jurkat T cells. 35 3.3. Requirement of the Shb SH2 domain for NFAT activation and IL-2 gene transcription 37 3.4. Subcellular localization of Shb upon T cell receptor engagement. 38 3.5. Association of Shb with the IL-2 receptor signaling complex. 38 3.6. A physiological role for Shb in IL-2 receptor signaling and regulation of apoptosis. 41 3.7. A role for the Shf adapter protein in PDGF-receptor signaling and cell survival. 43 4. CONCLUSIONS 45 ACKNOWLEDGEMENTS 46 5. REFERENCES 48 5 Abbreviations used: TCR T cell receptor BCR B cell receptor LAT linker for activation of T cells PLC-γ1 phospholipase C-γ1 ZAP70 zeta-associated protein-70 PI3K Phosphatidyl inositol-3 kinase PDGF Platelet-derived growth factor PDGFR Platelet-derived growth factor receptor FGF fibroblast growth factor NGF Nerve growth factor SH2 Src homology 2 SH3 Src homology 3 PTB phosphotyrosine binding PH Pleckstrin homology MAPK mitogen-activated protein kinase NFAT nuclear factor for activation of T cells AP-1 activating protein-1 NF-κB Nuclear factor κB PTK protein tyrosine kinase ITAM immunoreceptor tyrosine–based activation motif ERK extra-cellular signal-regulated protein kinase IL-2 Interleukin-2 IL-2R Interleukin-2 receptor GM-CSF Granulocyte-Macrophage colony stimulating factor ECL enhanced chemiluminescence system CAT chloramphenicol acetyltransferase NRS normal rabbit serum PBS phosphate-buffered saline PAGE polyacrylamide gel electrophoresis BSA bovine serum albumin JNK c-Jun N-terminal kinase JAK Janus kinase STAT signal transducer and activator of transcription GST glutathione-S-transferase P-Y phosphotyrosine GEMs Glycolipid-enriched membrane microdomain GDP Guanosine-di-phosphate GTP Guanosine-tri-phosphate PHA phytohemagglutinin NK Natural Killer DMEM Dulbecco’s Modified Eagle Media WT Wild type MHC major histocompatibility complex 6 Introduction INTRODUCTION A multicellular organism is composed of a variety of specialized cells, each with its own place and function in the organism. Both development and homeostasis of an organism requires strict regulation, that controls cell growth, differentiation, survival and death, generally referred to as cell signaling. This includes cell-cell contacts, activation of receptors and intracellular signal transducers, like kinases, phosphatases and transcription factors. The cells in an organism are constantly exposed to signals, activating different pathways, leading to the transcription of several genes. The repertoire of expressed proteins, and their levels of expression in the cell, then determine the characteristics of the cell. The immune system is composed of several specialized cells, with the aim to protect the organism from infections caused by bacteria, virus or fungi. There are two types of immune responses, innate and acquired immunity. The acquired immune response is mediated by B and T cells, and as the name suggests, has the ability to adapt to the environment. In humans, diseases like SCID (Severe combined immunodeficiency) and AIDS (Acquired immunodeficiency syndrome) derive from T cell defects. SCID is caused by a genetic defect, while AIDS is acquired through a retrovirus. However, both these diseases are lethal, and implicate the significance of a functional immune system for survival of the organism. In my studies I have tried to elucidate a role for the Shb adapter protein in T cells. I have studied the importance of Shb for proper T cell receptor signaling and established a role for Shb in IL-2 receptor signaling. I have also studied the importance of the Shb-relative, Shf, in fibroblast function and regulation of apoptosis. 7 Introduction The aims of this thesis were: • To determine the role for Shb in T cell receptor signaling, and find possible Shb interaction partners in T cells. • To study the effects of the Shb SH2 domain mutant on T cell receptor signaling in T cells. • To identify a possible role for Shb in Interleukin-2 receptor signaling in T and NK cells. • To find Shb homologues and define a role for the Shb family of adapter proteins in cell signaling. 8 Background 1 BACKGROUND 1.1 Receptors and their ligands Factors outside the cell, such as growth factors, hormones or proteins on other cells, can effect intracellular events, such as cell growth, cell death (apoptosis), production of new proteins or changes in cell morphology. These factors are collectively referred to as ligands, and they have the ability to associate with their cognate receptors. My focus here will be on tyrosine kinase receptors, hematopoietic receptors and cytokine receptors. 1.2 Tyrosine kinase receptors The PDGF receptors are examples of tyrosine kinase receptors. The tyrosine kinase receptors are transmembrane proteins with the ability to dimerize upon binding to their ligands which brings the two subunits in close contact with each other. These receptors have usually kinase domains with the ability to autophosphorylate tyrosines on the receptor itself and tyrosines on proteins that associate to the receptor. The PDGF receptor has two homologous isoforms, α and β which can form homo- or heterodimers (αα, ββ or αβ receptors), upon PDGF binding.
Load more

Recommended publications
  • Effects and Mechanisms of Eps8 on the Biological Behaviour of Malignant Tumours (Review)
    824 ONCOLOGY REPORTS 45: 824-834, 2021 Effects and mechanisms of Eps8 on the biological behaviour of malignant tumours (Review) KAILI LUO1, LEI ZHANG2, YUAN LIAO1, HONGYU ZHOU1, HONGYING YANG2, MIN LUO1 and CHEN QING1 1School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500; 2Department of Gynecology, Yunnan Tumor Hospital and The Third Affiliated Hospital of Kunming Medical University; Kunming, Yunnan 650118, P.R. China Received August 29, 2020; Accepted December 9, 2020 DOI: 10.3892/or.2021.7927 Abstract. Epidermal growth factor receptor pathway substrate 8 1. Introduction (Eps8) was initially identified as the substrate for the kinase activity of EGFR, improving the responsiveness of EGF, which Malignant tumours are uncontrolled cell proliferation diseases is involved in cell mitosis, differentiation and other physiological caused by oncogenes and ultimately lead to organ and body functions. Numerous studies over the last decade have demon- dysfunction (1). In recent decades, great progress has been strated that Eps8 is overexpressed in most ubiquitous malignant made in the study of genes and signalling pathways in tumours and subsequently binds with its receptor to activate tumorigenesis. Eps8 was identified by Fazioli et al in NIH-3T3 multiple signalling pathways. Eps8 not only participates in the murine fibroblasts via an approach that allows direct cloning regulation of malignant phenotypes, such as tumour proliferation, of intracellular substrates for receptor tyrosine kinases (RTKs) invasion, metastasis and drug resistance, but is also related to that was designed to study the EGFR signalling pathway. Eps8 the clinicopathological characteristics and prognosis of patients.
    [Show full text]
  • Insights Into Functional Connectivity in Mammalian Signal Transduction Pathways by Pairwise
    bioRxiv preprint doi: https://doi.org/10.1101/2019.12.30.891200; this version posted December 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Insights into Functional Connectivity in Mammalian Signal Transduction Pathways by Pairwise Comparison of Protein Interaction Partners of Critical Signaling Hubs Chilakamarti V. Ramana * Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03766, USA *Correspondence should be addressed: Chilakamarti V .Ramana, Telephone. (603)-738-2507, E-mail: [email protected] ORCID ID: /0000-0002-5153-8252 1 bioRxiv preprint doi: https://doi.org/10.1101/2019.12.30.891200; this version posted December 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Growth factors and cytokines activate signal transduction pathways and regulate gene expression in eukaryotes. Intracellular domains of activated receptors recruit several protein kinases as well as transcription factors that serve as platforms or hubs for the assembly of multi-protein complexes. The signaling hubs involved in a related biologic function often share common interaction proteins and target genes. This functional connectivity suggests that a pairwise comparison of protein interaction partners of signaling hubs and network analysis of common partners and their expression analysis might lead to the identification of critical nodes in cellular signaling.
    [Show full text]
  • The Role of the Src Homology-2 Domain Containing Protein B (SHB) in B Cells
    M WELSH and others Role of SHB in b cells 56:1 R21–R31 Review The role of the Src Homology-2 domain containing protein B (SHB) in b cells Correspondence † Michael Welsh, Maria Jamalpour, Guangxiang Zang and Bjo¨rn Åkerblom should be addressed to M Welsh Department of Medical Cell Biology, Uppsala University, PO Box 571, Husargatan 3, SE-75123 Uppsala, Sweden Email †G Zang is now at Department of Medical Biosciences, Umea˚ University, Umea˚ , Sweden [email protected] Abstract This review will describe the SH2-domain signaling protein Src Homology-2 domain Key Words containing protein B (SHB) and its role in various physiological processes relating in " signal transduction particular to glucose homeostasis and b cell function. SHB operates downstream of several " insulin secretion tyrosine kinase receptors and assembles signaling complexes in response to receptor " vascular activation by interacting with other signaling proteins via its other domains (proline-rich, " islet cells phosphotyrosine-binding and tyrosine-phosphorylation sites). The subsequent responses " immune system are context-dependent. Absence of Shb in mice has been found to exert effects on hematopoiesis, angiogenesis and glucose metabolism. Specifically, first-phase insulin secretion in response to glucose was impaired and this effect was related to altered characteristics of focal adhesion kinase activation modulating signaling through Akt, ERK, b catenin and cAMP. It is believed that SHB plays a role in integrating adaptive responses to various stimuli by simultaneously modulating cellular responses in different cell-types, thus Journal of Molecular Journal of Molecular Endocrinology playing a role in maintaining physiological homeostasis. Endocrinology (2016) 56, R21–R31 Introduction The limited replicative capacity of human pancreatic (bTC1 cells) after serum-stimulation, the Src Homology-2 b cells contributes significantly to the development of domain containing adapter protein B (SHB) was identified diabetes mellitus and thus comprises a major hurdle for (Welsh et al.
    [Show full text]
  • EPS8, an Adaptor Protein Acts As an Oncoprotein in Human Cancer
    Chapter 5 EPS8, an Adaptor Protein Acts as an Oncoprotein in Human Cancer Ming-Chei Maa and Tzeng-Horng Leu Additional information is available at the end of the chapter http://dx.doi.org/10.5772/54906 1. Introduction A spectrum of cellular activities including proliferation, differentiation and metabolism are controlled by growth factors and hormones. The effects of many growth factors are mediated and achieved via transmembrane receptor tyrosine kinases [1,2]. Following ligand binding, the intrinsic catalytic activity of the growth factor receptor tyrosine kinases (RTKs) is augmented. The autophosphorylated RTKs then transmit signals through their ability to recruit and/or phosphorylate intracellular substrates. Thus, identification and characterization of proteins that associate with and/or become tyrosyl phosphorylated by RTKs become critical to delineate RTKs-mediated signaling pathways. A variety of methodologies have been developed and applied to search for substrates of tyrosine kinases including RTKs [3-8]. Here, we focus on EGFR pathway substrate no. 8 (Eps8), a putative target of epidermal growth factor (EGF) receptor (EGFR), and discuss its biological function as well as its implication in human cancers. Given Eps8-elicited effects contribute to neoplasm, its potential as a therapeutic target for cancer treatment is anticipated. 1.1. The identification of Eps8 To dissect EGFR-mediated signaling, Di Fiore’s laboratory took advantage of immuno- affinity purification of an entire set of proteins phosphorylated in EGF-treated EGFR- overexpressing cells, followed by generation of antisera against the purified protein pool. With these antisera, bacterial expression libraries were immunologically screened. Several murine cDNAs (eps clones) representing genes encoding substrates for EGFR were obtained [7,8].
    [Show full text]
  • The Clinical Aspect of Adaptor Molecules in T Cell Signaling: Lessons Learnt from Inborn Errors of Immunity
    MINI REVIEW published: 12 August 2021 doi: 10.3389/fimmu.2021.701704 The Clinical Aspect of Adaptor Molecules in T Cell Signaling: Lessons Learnt From Inborn Errors of Immunity Yael Dinur-Schejter 1,2,3*, Irina Zaidman 1,2, Hagar Mor-Shaked 1,4 and Polina Stepensky 1,2 1 Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel, 2 The Bone Marrow Transplantation and Cancer Immunotherapy Department, Hadassah Ein Kerem Medical Center, Jerusalem, Israel, 3 Allergy and Clinical Immunology Unit, Hadassah Ein-Kerem Medical Center, Jerusalem, Israel, 4 Monique and Jacques Roboh Department of Genetic Research, Hadassah Ein Kerem Medical Center, Jerusalem, Israel Adaptor molecules lack enzymatic and transcriptional activities. Instead, they exert their function by linking multiple proteins into intricate complexes, allowing for transmitting and fine-tuning of signals. Many adaptor molecules play a crucial role in T-cell signaling, following engagement of the T-cell receptor (TCR). In this review, we focus on Linker of Edited by: Activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 KDa (SLP- Anne Spurkland, 76). Monogenic defects in these adaptor proteins, with known roles in T-cell signaling, University of Oslo, Norway have been described as the cause of human inborn errors of immunity (IEI). We describe Reviewed by: Martha Jordan, the current knowledge based on defects in cell lines, murine models and human patients. University of Pennsylvania, Germline mutations in Adhesion and degranulation adaptor protein (ADAP), have not United States resulted in a T-cell defect. Stephen Charles Bunnell, Tufts University School of Medicine, Keywords: adaptor molecules, ADAP, LAT, SLP-76, T-cell signaling, primary immune deficiency United States *Correspondence: Yael Dinur-Schejter [email protected] INTRODUCTION Specialty section: Engagement of the T cell receptor (TCR) triggers a signaling cascade responsible for T-cell This article was submitted to activation, maturation and differentiation.
    [Show full text]
  • Phenotype Informatics
    Freie Universit¨atBerlin Department of Mathematics and Computer Science Phenotype informatics: Network approaches towards understanding the diseasome Sebastian Kohler¨ Submitted on: 12th September 2012 Dissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) am Fachbereich Mathematik und Informatik der Freien Universitat¨ Berlin ii 1. Gutachter Prof. Dr. Martin Vingron 2. Gutachter: Prof. Dr. Peter N. Robinson 3. Gutachter: Christopher J. Mungall, Ph.D. Tag der Disputation: 16.05.2013 Preface This thesis presents research work on novel computational approaches to investigate and characterise the association between genes and pheno- typic abnormalities. It demonstrates methods for organisation, integra- tion, and mining of phenotype data in the field of genetics, with special application to human genetics. Here I will describe the parts of this the- sis that have been published in peer-reviewed journals. Often in modern science different people from different institutions contribute to research projects. The same is true for this thesis, and thus I will itemise who was responsible for specific sub-projects. In chapter 2, a new method for associating genes to phenotypes by means of protein-protein-interaction networks is described. I present a strategy to organise disease data and show how this can be used to link diseases to the corresponding genes. I show that global network distance measure in interaction networks of proteins is well suited for investigat- ing genotype-phenotype associations. This work has been published in 2008 in the American Journal of Human Genetics. My contribution here was to plan the project, implement the software, and finally test and evaluate the method on human genetics data; the implementation part was done in close collaboration with Sebastian Bauer.
    [Show full text]
  • Lineage-Specific Effector Signatures of Invariant NKT Cells Are Shared Amongst Δγ T, Innate Lymphoid, and Th Cells
    Downloaded from http://www.jimmunol.org/ by guest on September 26, 2021 δγ is online at: average * The Journal of Immunology , 10 of which you can access for free at: 2016; 197:1460-1470; Prepublished online 6 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600643 http://www.jimmunol.org/content/197/4/1460 Lineage-Specific Effector Signatures of Invariant NKT Cells Are Shared amongst T, Innate Lymphoid, and Th Cells You Jeong Lee, Gabriel J. Starrett, Seungeun Thera Lee, Rendong Yang, Christine M. Henzler, Stephen C. Jameson and Kristin A. Hogquist J Immunol cites 41 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2016/07/06/jimmunol.160064 3.DCSupplemental This article http://www.jimmunol.org/content/197/4/1460.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 26, 2021. The Journal of Immunology Lineage-Specific Effector Signatures of Invariant NKT Cells Are Shared amongst gd T, Innate Lymphoid, and Th Cells You Jeong Lee,* Gabriel J.
    [Show full text]
  • Genome-Wide Association Analysis of the Genetic Basis for Sheath Blight Resistance in Rice
    Zhang et al. Rice (2019) 12:93 https://doi.org/10.1186/s12284-019-0351-5 ORIGINAL ARTICLE Open Access Genome-Wide Association Analysis of the Genetic Basis for Sheath Blight Resistance in Rice Fan Zhang, Dan Zeng, Cong-Shun Zhang, Jia-Ling Lu, Teng-Jun Chen, Jun-Ping Xie and Yong-Li Zhou* Abstract Background: Sheath blight (ShB), caused by Rhizoctonia solani Kühn, is one of the most destructive rice diseases. Developing ShB-resistant rice cultivars represents the most economical and environmentally sound strategy for managing ShB. Results: To characterize the genetic basis for ShB resistance in rice, we conducted association studies for traits related to ShB resistance, namely culm length (CL), lesion height (LH), and relative lesion height (RLH). Combined a single locus genome-wide scan and a multi-locus method using 2,977,750 single-nucleotide polymorphisms to analyse 563 rice accessions, we detected 134, 562, and 75 suggestive associations with CL, LH, and RLH, respectively. The adjacent signals associated with RLH were merged into 27 suggestively associated loci (SALs) based on the estimated linkage disequilibrium blocks. More than 44% of detected RLH-SALs harboured multiple QTLs/genes associated with ShB resistance, while the other RLH-SALs were putative novel ShB resistance loci. A total of 261 ShB resistance putative functional genes were screened from 23 RLH-SALs according to bioinformatics and haplotype analyses. Some of the annotated genes were previously reported to encode defence-related and pathogenesis-related proteins, suggesting that quantitative resistance to ShB in rice is mediated by SA- and JA- dependent signalling pathways.
    [Show full text]
  • The Role of the Src Homology-2 Domain Containing Protein B (SHB) in B Cells
    M WELSH and others Role of SHB in b cells 56:1 R21–R31 Review The role of the Src Homology-2 domain containing protein B (SHB) in b cells Correspondence † Michael Welsh, Maria Jamalpour, Guangxiang Zang and Bjo¨rn Åkerblom should be addressed to M Welsh Department of Medical Cell Biology, Uppsala University, PO Box 571, Husargatan 3, SE-75123 Uppsala, Sweden Email †G Zang is now at Department of Medical Biosciences, Umea˚ University, Umea˚ , Sweden [email protected] Abstract This review will describe the SH2-domain signaling protein Src Homology-2 domain Key Words containing protein B (SHB) and its role in various physiological processes relating in " signal transduction particular to glucose homeostasis and b cell function. SHB operates downstream of several " insulin secretion tyrosine kinase receptors and assembles signaling complexes in response to receptor " vascular activation by interacting with other signaling proteins via its other domains (proline-rich, " islet cells phosphotyrosine-binding and tyrosine-phosphorylation sites). The subsequent responses " immune system are context-dependent. Absence of Shb in mice has been found to exert effects on hematopoiesis, angiogenesis and glucose metabolism. Specifically, first-phase insulin secretion in response to glucose was impaired and this effect was related to altered characteristics of focal adhesion kinase activation modulating signaling through Akt, ERK, b catenin and cAMP. It is believed that SHB plays a role in integrating adaptive responses to various stimuli by simultaneously modulating cellular responses in different cell-types, thus Journal of Molecular Journal of Molecular Endocrinology playing a role in maintaining physiological homeostasis. Endocrinology (2016) 56, R21–R31 Introduction The limited replicative capacity of human pancreatic (bTC1 cells) after serum-stimulation, the Src Homology-2 b cells contributes significantly to the development of domain containing adapter protein B (SHB) was identified diabetes mellitus and thus comprises a major hurdle for (Welsh et al.
    [Show full text]
  • Gene Expression Profiling in Fibromyalgia Indicates An
    Journal of Clinical Medicine Article Gene Expression Profiling in Fibromyalgia Indicates an Autoimmune Origin of the Disease and Opens New Avenues for Targeted Therapy 1 1 2, 1, , Marzia Dolcino , Elisa Tinazzi , Antonio Puccetti y and Claudio Lunardi * y 1 Department of Medicine, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy; [email protected] (M.D.); [email protected] (E.T.) 2 Department of Experimental Medicine, Section of Histology, University of Genova, Via G.B. Marsano 10, 16132 Genova, Italy; [email protected] * Correspondence: [email protected] These authors contributed equally to this work. y Received: 29 April 2020; Accepted: 7 June 2020; Published: 10 June 2020 Abstract: Fibromyalgia is a chronic disorder characterized by widespread pain and by several non-pain symptoms. Autoimmunity, small fiber neuropathy and neuroinflammation have been suggested to be involved in the pathogenesis of the disease. We have investigated the gene expression profile in peripheral blood mononuclear cells obtained from ten patients and ten healthy subjects. Of the 545,500 transcripts analyzed, 1673 resulted modulated in fibromyalgic patients. The majority of these genes are involved in biological processes and pathways linked to the clinical manifestations of the disease. Moreover, genes involved in immunological pathways connected to interleukin-17 and to Type I interferon signatures were also modulated, suggesting that autoimmunity plays a role in the disease. We then aimed at identifying differentially expressed Long non-coding RNAs (LncRNAs) functionally connected to modulated genes both directly and via microRNA targeting. Only two LncRNAs of the 298 found modulated in patients, were able to target the most highly connected genes in the fibromyalgia interactome, suggesting their involvement in crucial gene regulation.
    [Show full text]
  • Haplotyping Small Hive Beetle (Aethina Tumida) Reveals NA1 and NA2 Distribution in Rhode Island Apis Mellifera Hives Katelyn St
    Rhode Island College Digital Commons @ RIC Honors Projects Overview Honors Projects 2017 Haplotyping Small Hive Beetle (Aethina Tumida) Reveals NA1 and NA2 Distribution in Rhode Island Apis Mellifera Hives Katelyn St. George [email protected] Follow this and additional works at: https://digitalcommons.ric.edu/honors_projects Part of the Biology Commons Recommended Citation St. George, Katelyn, "Haplotyping Small Hive Beetle (Aethina Tumida) Reveals NA1 and NA2 Distribution in Rhode Island Apis Mellifera Hives" (2017). Honors Projects Overview. 135. https://digitalcommons.ric.edu/honors_projects/135 This Honors is brought to you for free and open access by the Honors Projects at Digital Commons @ RIC. It has been accepted for inclusion in Honors Projects Overview by an authorized administrator of Digital Commons @ RIC. For more information, please contact [email protected]. Haplotyping small hive beetle 3 HAPLOTYPING SMALL HIVE BEETLE (AETHINA TUMIDA) REVEALS NA1 AND NA2 DISTRIBUTION IN RHODE ISLAND APIS MELLIFERA HIVES By Katelyn St. George An Undergraduate Thesis Submitted in Partial Fulfillment of the Requirements for the Awarding of Departmental Honors in the Department of Biology The Faculty of Arts and Sciences Rhode Island College 2017 Haplotyping small hive beetle 4 ABSTRACT The small hive beetle (Aethina tumida) is a parasite of honeybee hives (Apis mellifera) and native to South Africa. Invasive in North America since 1996, the species has spread to hives throughout the continent, including many in Rhode Island and nearby states. To better understand migration patterns for this invasive species, we haplotyped small hive beetles (SHB) based on mitochondrial Cytochrome Oxidase Part 1 (COI) gene sequences.
    [Show full text]
  • BMC Immunology
    BMC Immunology This Provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. Shb deficient mice display an augmented TH2 response in peripheral CD4+ T cells BMC Immunology 2011, 12:3 doi:10.1186/1471-2172-12-3 Karin Gustafsson ([email protected]) Gabriela Calounova ([email protected]) Fredrik Hjelm ([email protected]) Vitezslav Kriz ([email protected]) Birgitta Heyman ([email protected]) Kjell-Olov Gronvik ([email protected]) Gustavo Mostoslavsky ([email protected]) Michael Welsh ([email protected]) ISSN 1471-2172 Article type Research article Submission date 10 December 2010 Acceptance date 11 January 2011 Publication date 11 January 2011 Article URL http://www.biomedcentral.com/1471-2172/12/3 Like all articles in BMC journals, this peer-reviewed article was published immediately upon acceptance. It can be downloaded, printed and distributed freely for any purposes (see copyright notice below). Articles in BMC journals are listed in PubMed and archived at PubMed Central. For information about publishing your research in BMC journals or any BioMed Central journal, go to http://www.biomedcentral.com/info/authors/ © 2011 Gustafsson et al. ; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided
    [Show full text]