Regulation of Leukocyte Integrin Binding to Ig-Family Ligands
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Recent Publications in this Series LIISA UOTILA Regulation of Leukocyte Integrin Binding to Ig-Family Ligands 17/2014 Anita Wasik Molecular Mechanisms Regulating Glucose Uptake into Podocytes: Role of Ezrin, Septin 7 and Nonmuscle Myosin IIA 18/2014 Karita Peltonen Small Molecule Modulators of Tumor Suppressor p53 and RNA Polymerase I Activity: Identifi cation, Anticancer Activity and Mechanism of Action DISSERTATIONES SCHOLAE DOCTORALIS AD SANITATEM INVESTIGANDAM 19/2014 Aino Sesilja Aranko UNIVERSITATIS HELSINKIENSIS 37/2014 Intermolecular Protein Splicing and Its Use in Biotechnological Applications 20/2014 Rahul Raj Prognostic Models in Traumatic Brain Injury 21/2014 Mikko Nieminen Candida Yeasts and Carcinogenic Acetaldehyde in Upper Digestive Tract Carcinogenesis 22/2014 Janne Hakanen LIISA UOTILA Molecular Regulation of Forebrain Development and Neural Stem/Progenitor Cells 23/2014 Kari-Pekka Skarp Dynamics of Nuclear Actin Regulation of Leukocyte Integrin Binding to 24/2014 Linda Ahonen Method Development for the Analysis of Steroids, Vitamin D and Oxysterols Ig-Family Ligands 25/2014 Jenni Liljavirta Bovine B Cells: Antibody Repertoire Diversifi cation in Fetal Cattle 26/2014 Denis Đermadi Bebek Biochemical Effects of Inherited MMR Gene Mutations and Diet on Colon Cancer Risk 27/2014 Helka Sahi Subgroups of Merkel Cell Carcinoma Patients Defi ned by Young Age, Immunodefi ciency and Polyomavirus Infection 28/2014 Heidi Sillanpää Novel Immunological Markers of Lyme Borreliosis 29/2014 Tuomas Herva Animal Welfare and Economics in Beef Production 30/2014 Sofi a Ahola Diagnosis and Therapy for Mitochondrial Diseases 31/2014 Johanna Mattsson Antiangiogenic and Proteolytic Activities of Prostate-Specifi c Antigen 32/2014 Olli Pietiläinen Rare Genomic Deletions Underlying Schizophrenia and Related Neurodevelopmental Disorders 33/2014 Salla Jaakkola Evolution in Salt: Genomic and Structural Approaches to Halophilic archaea and Their Viruses 34/2014 Kati Ahlqvist The Effects of Mitochondrial DNA Mutagenesis on Somatic Stem Cells and Ageing 35/2014 Liisa Lilja-Maula Canine Idiopathic Pulmonary Fibrosis in West Highland White Terriers: DIVISION OF BIOCHEMISTRY AND BIOTECHNOLOGY Natural History of the Disease and TGF-β Related Molecular Pathways DEPARTMENT OF BIOSCIENCES Involved 36/2014 Saija Ahonen FACULTY OF BIOLOGICAL AND ENVIRONMENTAL SCIENCES Canine Models of Human Vision Disorders: Identifi cation of New Loci DOCTORAL PROGRAMME IN INTEGRATIVE LIFE SCIENCE and Genes for Glaucoma and Retinal Degeneration UNIVERSITY OF HELSINKI 37/2014 Helsinki 2014 ISSN 2342-3161 ISBN 978-951-51-0338-3 ccover.inddover.indd 1 222.10.20142.10.2014 77:29:55:29:55 RegulaƟ on of leukocyte integrin binding to Ig-family ligands Liisa UoƟ la Division of Biochemistry and Biotechnology Department of Biosciences Faculty of Biological and Environmental Sciences and Integrative Life Sciences Doctoral Program University of Helsinki ACADEMIC DISSERTATION To be presented for public examination with the permission of the Faculty of Biological and Environmental Sciences of the University of Helsinki in the lecture hall B2 of Viikki B-building (VI B LS 2), Latokartanonkaari 7, on 21st November at 12 noon. Helsinki 2014 Supervisor Carl Gahmberg, professor Division of Biochemistry and Biotechnology Department of Biosciences Faculty of Biological and Environmental Sciences University of Helsinki Reviewers Jorma Keski-Oja, professor Translational Cancer Biology Research Program Haartman Institute University of Helsinki Manuel Patarroyo, professor Department of Dental Medicine Karolinska Institutet Stockholm, Sweden Opponent Francisco Sánchez-Madrid, professor Servicio de Inmunología, Hospital de la Princesa Instituto de Investigación Sanitaria de la Princesa Universidad Autónoma de Madrid Madrid, Spain Custos Jukka Finne, professor Division of Biochemistry and Biotechnology Department of Biosciences Faculty of Biological and Environmental Sciences University of Helsinki Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis ISBN 978-951-51-0338-3 (paperback) ISSN 2342-3161 (print) ISBN 978-951-51-0339-0 (PDF) ISSN2342-317X (Online) http://ethesis.helsinki.fi Layout: Tinde Päivärinta/PSWFolders Oy Hansaprint Oy, Vantaa, Finland 2014 Le plus grand bonheur de l’étude consiste à trouver les raisons soi-même. René Descartes Table of contents Original publications Abbreviations Summary REVIEW OF THE LITERATURE .......................................................................................................1 1 Introduction to blood cell adhesion .............................................................................................1 1.1 Interactions of erythrocytes with other cells and ECM .......................................................1 1.1.1 Erythropoiesis ...............................................................................................................1 1.1.2 Erythrophagocytosis, removal of senescent red cells ..............................................3 1.1.3 Pathological conditions of red blood cell adhesion .................................................3 1.2 Leukocyte adhesion ..................................................................................................................4 1.2.1 Th e immunological synapse ........................................................................................4 1.2.2 Extravasation .................................................................................................................6 1.2.3 Phagocytosis ..................................................................................................................7 1.2.4 Pathological conditions involving leukocyte adhesion ...........................................8 1.3 Haemostasis and thrombosis ..................................................................................................9 2 Th e Ig-superfamily ...........................................................................................................................9 2.1 ICAM family members are important in leukocyte adhesion ............................................9 2.2 ICAM-4 ....................................................................................................................................11 2.2.1 Th e LW blood group antigen is ICAM-4 (CD242) ................................................11 2.2.2 ICAM-4 contains two Ig domains ............................................................................12 2.2.3 Ligands and functions of ICAM-4 ...........................................................................13 2.3 VCAM-1 ..................................................................................................................................15 3 Leukocyte integrins .......................................................................................................................15 3.1 Introduction ..........................................................................................................................15 3.2 Integrin structure and conformational changes .................................................................16 3.3 LFA-1 (αLβ2, CD11a/CD18) .................................................................................................19 3.4 Mac-1 (αMβ2, CD11b/CD18, CR3) .....................................................................................19 3.5 αDβ2 .......................................................................................................................................20 3.6 VLA-4 (α4β1, CD49d/CD29) ...............................................................................................20 3.7 Th e β7 integrins αEβ7 and α4β7 ...........................................................................................21 3.8 CR4 (αXβ2, CD11c/CD18, p150.95) ....................................................................................21 3.8.1 Structure ......................................................................................................................21 3.8.2 Ligands and functions of CR4 ..................................................................................22 4 Regulation of integrin activity ....................................................................................................25 4.1 Affi nity/avidity ........................................................................................................................25 4.2 Inside-out activation of integrins .........................................................................................26 4.3 Outside-in signalling initiated by integrin ligand binding ...............................................29 4.4 Phosphorylation .....................................................................................................................33 4.4.1 β2 integrins ..................................................................................................................33 4.4.2 VLA-4 ...........................................................................................................................34 4.5 Transdominant regulation of integrins ................................................................................35 4.5.1 Leukocyte integrins ....................................................................................................35 4.5.2 Other integrins in cross talk .....................................................................................36 SUMMARY OF THE STUDY