Biophysical Aspects of Transmembrane Signaling

CHAPTER 1 The Impact of Environmental Signals on the Growth and Survival of Human T Cells . . . . . . . . . . . . . . . . . . . . . . . . . 1 Fernando A. Arosa,Ana M. Fonseca, Susana G. Santos, Nuno L.Alves 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Red Blood Cells: From Carriers of Respiratory Gases to Modulators of T Cell Survival . . . . . . . . . . . . . . . . . . . . 1 1.2.1 RBC: Carriers of O2 and CO2 . . . . . . . . . . . . . . . . . . . . . . 1 1.2.2 Novel Functions of RBC . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.2.3 Are Transmembrane Signals Involved in the Regulation of T Cell Survival Induced by RBC? . . . . . . . . . . . . . . . . . . 4 1.2.4 Are RBC-Derived Vesicles Carriers of the RBC Bioactivity? . . . . . 6 1.3 Epithelial Cells and IL-15: The Perfect Combination for CD8+ T Cell Differentiation . . . . . . . . . . . . . . . . . . . . 7 1.3.1 Interleukin-15: Major Features of a Multifunctional Cytokine . . . . 7 1.3.2 Physiological Expression of IL-15: The Epithelial Cell Connection . . . . . . . . . . . . . . . . . . . . . 9 1.3.3 Epithelial Tissues as Sites for CD8+ T Cell Positioning and Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1.3.4 Epithelial Cells Deliver Activation and Survival Signals Preferentially to CD8+ T Cells . . . . . . . . . . . . . . . . . . . . . 11 1.4 MHC-Class I Molecules: Pleiotropic Transmembrane Signaling Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1.4.1 The MHC Locus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1.4.2 Folding and Assembly of MHC-Class I Molecules . . . . . . . . . . 13 1.4.3 Cell-Surface MHC-Class I Molecules: trans Interactions with the TCR and NK Receptors . . . . . . . . . . . . . . . . . . . . 13 1.4.4 Cell-Surface MHC-Class I Molecules: cis Interactions with Growth Receptors . . . . . . . . . . . . . . . . . . . . . . . . . 15 1.4.5 Cell-Surface MHC-Class I Molecules in T Cells: Are Misfolding and cisAssociation Related Events? . . . . . . . . . 16 1.4.6 MHC-Class I cis Associations and the Regulation of T Cell Growth and Survival . . . . . . . . . . . . . . . . . . . . . 17 1.5 Concluding Remarks and Future Prospects . . . . . . . . . . . . . . 18 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 VII Contents VIII Contents CHAPTER 2 Novel Single Cell Fluorescence Approaches in the Investigation of Signaling at the Cellular Level . . . . . . . . . . . 33 Péter Nagy, György Vereb, Janine N. Post, Elza Friedländer, János Szöll´o´si 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 2.2 Subcellular and Temporal Resolution vs. Statistical Reliability . . . 33 2.3 Labeling of Cells with Fluorescent Molecules . . . . . . . . . . . . . 35 2.3.1 Monoclonal Antibodies and Their Derivatives . . . . . . . . . . . . 35 2.3.2 Visible Fluorescent Proteins. . . . . . . . . . . . . . . . . . . . . . . 36 2.3.3 Novel Applications of VFPs in Cell Biology . . . . . . . . . . . . . . 40 2.3.4 Labeling of Tetracysteine Motifs with Biarsenical Derivatives of Fluorophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 2.3.5 Quantum Dots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 2.3.6 Steric Effects of Fluorescent Labeling . . . . . . . . . . . . . . . . . 45 2.4 Methods to Detect Fluorescence in Cell Biological Applications. . . . 46 2.4.1 Spatial Resolution of Fluorescence Microscopy . . . . . . . . . . . . 46 2.4.2 Confocal Microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . 47 2.4.3 Multiphoton Microscopy . . . . . . . . . . . . . . . . . . . . . . . . 47 2.4.4 Focusing Microscopes Breaking the Abbe Limit . . . . . . . . . . . 48 2.4.5 Scanning Near-Field Optical Microscopy (SNOM) . . . . . . . . . . 49 2.5 Fluorescence Resonance Energy Transfer (FRET) . . . . . . . . . . 49 2.5.1 A Brief Introduction to FRET. . . . . . . . . . . . . . . . . . . . . . 49 2.5.2 Different Ways to Measure FRET . . . . . . . . . . . . . . . . . . . . 51 2.5.2.1 Donor Quenching, Sensitized Emission of the Acceptor . . . . . . . 51 2.5.2.2 Acceptor Photobleaching, Photochromic FRET . . . . . . . . . . . . 52 2.5.2.3 Donor Photobleaching. . . . . . . . . . . . . . . . . . . . . . . . . . 53 2.5.2.4 FRET-Sensitized Photobleaching of the Acceptor. . . . . . . . . . . 53 2.5.2.5 Combined Donor and Acceptor Emission Measurements . . . . . . 54 2.5.2.6 FRET Between Spectroscopically Identical Molecules . . . . . . . . 55 2.6 Cell Biophysical Methods Reveal Molecular Interactions in the ErbB Signaling Pathway . . . . . . . . . . . . . . . . . . . . . 56 2.6.1 Small-Scale Associations: Homo- and Heterodimerization in the ErbB Family. . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 2.6.2 Large-Scale Associations of ErbB Proteins. . . . . . . . . . . . . . . 57 2.6.3 Focal Stimulation of Cells with Magnetic Beads . . . . . . . . . . . 58 2.6.4 Image Cytometry in Assessing the Activation State of ErbB Receptor Tyrosine Kinases. . . . . . . . . . . . . . . . . . . 60 2.6.5 Following the Internalization of Receptors Using Fluorescence Approaches . . . . . . . . . . . . . . . . . . . . . . . . 61 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Contents IX CHAPTER 3 Non-Random Patterns of Membrane Proteins and Their Roles in Transmembrane Signaling . . . . . . . . . . . . . . . . 71 Andrea Bodnár, György Vámosi, Katalin Tóth,Attila Jenei, László Mátyus, Sándor Damjanovich 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 3.2 Fluorescence Resonance Energy Transfer (FRET) . . . . . . . . . . 74 3.2.1 Measurement of FRET by Flow Cytometry . . . . . . . . . . . . . . 74 3.2.1.1 Sample Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3.2.1.2 Signals and Calculations. . . . . . . . . . . . . . . . . . . . . . . . . 75 3.3 Mapping the Distribution of Cell-Surface Proteins . . . . . . . . . . 77 3.3.1 Self-Association of MHC I Molecules . . . . . . . . . . . . . . . . . 77 3.3.2 Heteroassociation of MHC I Glycoproteins . . . . . . . . . . . . . . 79 3.3.3 Association Patterns of MHC I, MHC II and ICAM-1 Molecules . . 80 3.3.4 Supramolecular Complexes of IL-2/IL-15R and MHC Glycoproteins on Human T Lymphoma Cells . . . . . . . 81 3.4 Fluorescence Correlation Spectroscopy (FCS). . . . . . . . . . . . . 82 3.4.1 Instrumentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 3.4.2 Evaluation of FCS Experiments. . . . . . . . . . . . . . . . . . . . . 88 3.4.3 The Co-mobility of IL-15Rα, IL-2Rα and MHC I Was Studied in FT7.10 Cells. . . . . . . . . . . . . . . . . . . . . . . 88 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 CHAPTER 4 Transmembrane Signals Mediated by IL-2 and IL-15 Control the Life and Death of Lymphocytes . . . . . . . . . . . 97 Thomas A.Waldmann, Sigrid Dubois, Jürgen Müller, Carolyn Goldman, Sándor Damjanovich 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 4.2 The Classical View of the IL-2 and IL-15 Receptor and Signaling Pathways That Underlie the Shared Functions of These Two Cytokines. . . . . . . . . . . . . . . . . . . 98 4.3 IL-15 Utilizes a Novel Receptor in Mast Cells . . . . . . . . . . . . . 101 4.4 The Shared and Contrasting Functions of IL-2 and IL-15 . . . . . . 101 4.5 Classical IL-2, IL-15 Signal Transduction Pathways That Underlie the Shared Roles of IL-2 and IL-15 . . . . . . . . . . 102 4.6 Suppressors of Cytokine Signaling . . . . . . . . . . . . . . . . . . . 104 4.7 The Distinct Receptor Signaling Pathways That Underlie the Contrasting Roles of IL-2 and IL-15 in the Life and Death of Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . 104 4.8 The Distinct Roles of IL-2 and IL-15 in Signaling for AICD . . . . . 107 4.8.1 AICD Signaling Downstream of Death Receptors. . . . . . . . . . . 108 4.9 Distinct Signals for Proliferation Mediated by IL-2 and IL-15 . . . . 109 4.9.1 The PI-3 K Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 4.9.2 The FKBP12.6 Pathway . . . . . . . . . . . . . . . . . . . . . . . . . 110 4.9.3 The MAPK Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 X Contents 4.10 Immunotherapy Targeted to the IL-2/IL-2R IL-15/IL-15R System . . 111 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 CHAPTER 5 Single-Molecule Imaging of Diffusion, Recruitment, and Activation of Signaling Molecules in Living Cells . . . . . . . . . . . 123 Akihiro Kusumi, Hideji Murakoshi, Kotono Murase, Takahiro Fujiwara 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 5.2 The 30-Year-Old Enigma Concerning the Diffusion Rate of Membrane Molecules in the Plasma Membrane . . . . . . . . . . 126 5.3 Corralling Effects of the Membrane Skeleton for Transmembrane Proteins (the Membrane-Skeleton Fence Model) . . . . . . . . . . . 127 5.4 Lipids Also Undergo Hop Diffusion in the Plasma Membrane. . . . . 133 5.5 Oligomerization-Induced Trapping . . . . . . . . . . . . . . . . . . 138 5.6 A Paradigm Shift of the Plasma Membrane Structure Concept Is Necessary: From the Simple Two-Dimensional Continuum Fluid Model to the Compartmentalized Fluid Model. . . . . . . . . 140 5.7 FRET Strategy for Detecting the Activation of Single Molecules of Ras . . . . . . . . . . . . . . . . . . . . . . . 140 5.8 Visualizing the Activation of Single Molecules of H-Ras in Living Cells . . . . . . . . . . . . . . . . . . . . . . . . . 142 5.9 Ras Diffusion Slows Upon Activation . . . . . . . . . . . . . . . . . 143 5.10 A Model for the Formation of the Active Ras Signal Transduction Complex. . . . . . . . . . . . . . . . . . . . . . 146 5.11 Recruitment of GAP334, the Ras-Binding, Catalytic Domain of p120RasGAP, on the Cell Membrane . . . . . . . . . . . . . . . . 147 5.12 Conclusions Regarding the FRET Method for Monitoring the Activation of Single Ras Molecules. . . . . . . . . . . . . . . . . 148 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 CHAPTER 6 Chemokine Signaling: The Functional Importance of Stabilizing Receptor Conformations . . . . . . . . . . . . . . . . . . . . 153 José Miguel Rodríguez-Frade,Antonio Serrano, Carlos Martínez-A, Mario Mellado 6.1 Chemokines and Their Receptors . . . . . . . . . . . . . . . . . . . 153 6.2 Signaling Through Chemokine Receptors . . . . . . . . . . . . . . . 154 6.2.1 Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 6.2.2 The Use of Biophysical Techniques to Measure Chemokine Receptor Oligomerization. . . . . . . . . . . . . . . . . . . . . . . . 155 6.2.3 Characterization of Chemokine Receptor Homo- and Heterodimerization . . . . . . . . . . . . . . . . . . . . 157 6.2.4 Chemokines Trigger JAK/STAT Pathway Activation . . . . . . . . . 161 6.2.5 Chemokine Signaling Involves G Protein Activation . . . . . . . . . 162 Contents XI 6.3 General Considerations on the Biophysical Aspects of Signaling . . 162 6.3.1 Receptor Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 6.3.2 Receptor Localization . . . . . . . . . . . . . . . . . . . . . . . . . . 163 6.4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . 164 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 CHAPTER 7 Signaling and Reverse Signaling in the Tumor Necrosis Factor/TNF Receptor System . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Ern´o´ Duda, Tünde Nagy, Daniela N. Männel, Günther Eissner 7.1 The TNF/TNFR System . . . . . . . . . . . . . . . . . . . . . . . . . 171 7.1.1 Evolution of the TNF/TNFR System . . . . . . . . . . . . . . . . . . 173 7.1.2 General Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 7.1.2.1 Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 7.1.2.2 Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 7.2 TNFR1 and the Apoptotic Signal . . . . . . . . . . . . . . . . . . . . 177 7.3 TNF Receptors and the Survival Signal . . . . . . . . . . . . . . . . 180 7.3.1 TNF Receptor-Associated Factors (TRAF1–7). . . . . . . . . . . . . 181 7.3.2 Signaling Pathways Activated by TRAFs . . . . . . . . . . . . . . . . 181 7.3.3 The NF-kappaB Pathway . . . . . . . . . . . . . . . . . . . . . . . . 183 7.3.4 The Role of Membrane Microdomains (Rafts) in the Formation of Signaling Complexes . . . . . . . . . . . . . . . 185 7.3.5 Activation of JNK . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 7.4 Signaling of Other Family Members . . . . . . . . . . . . . . . . . . 187 7.4.1 4-1BB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 7.4.2 BAFFR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 7.4.3 BCMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 7.4.4 CD27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 7.4.5 CD30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 7.4.6 CD40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 7.4.7 DR3/TRAMP and DcR3 . . . . . . . . . . . . . . . . . . . . . . . . . 191 7.4.8 DR4 and DR5 (TRAILR1 and R2) and Decoy Receptors DcR1 and DcR2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 7.4.9 EDAR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 7.4.10 Fas Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 7.4.11 GITR/AITR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 7.4.12 HVEM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 7.4.13 Lymphotoxin-βReceptor . . . . . . . . . . . . . . . . . . . . . . . . 194 7.4.14 RANK and Osteoprotegerin (OPG). . . . . . . . . . . . . . . . . . . 195 7.4.15 TACI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 7.4.16 TNFR2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 7.4.17 TWEAKR/Fn14. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 7.5 Reverse Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 7.6 Therapy/Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . 198 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 XII Contents CHAPTER 8 Regulation of Immunoreceptor Activities: The Paradigm of the Type I Fcε Receptor . . . . . . . . . . . . . . . . . . . 211 Jakub Abramson, Israel Pecht 8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 8.2 Type I Fcε Receptor (FcεRI)-Mediated Cell Responses. . . . . . . . 211 8.2.1 FcεRI Structure, Expression and Function . . . . . . . . . . . . . . 211 8.2.2 FcεRI Stimulus-Response Coupling Cascade on Mast Cells . . . . . 213 8.2.2.1 The “Original”Model . . . . . . . . . . . . . . . . . . . . . . . . . . 213 8.2.2.2 The Function of Monomeric IgE (mIgE). . . . . . . . . . . . . . . . 214 8.2.2.3 Lipid Rafts and FcεRI Activation. . . . . . . . . . . . . . . . . . . . 215 8.2.2.4 Lyn Activation and its Significance. . . . . . . . . . . . . . . . . . . 216 8.2.2.5 Fyn–Gab-2–PI3 K-Mediated Signaling. . . . . . . . . . . . . . . . . 217 8.2.2.6 The Syk–LAT–SLP-76 Signaling Pathway . . . . . . . . . . . . . . . 219 8.2.2.7 The (Btk)–PLC-γ–PKC Coupling Cascade . . . . . . . . . . . . . . . 221 8.2.2.8 The Role of MAP Kinases in FcεRI-Induced Gene Transcription . . 222 8.2.2.9 Overview of the Current Model of the FcεRI Stimulus-Response Coupling Network. . . . . . . . . . . . . . . . . 227 8.3 Mechanisms Regulating Response to the FcεRI Stimulus . . . . . . 229 8.3.1 Regulatory Cytosolic Molecules . . . . . . . . . . . . . . . . . . . . 229 8.3.1.1 Phosphatases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 8.3.1.2 Protein Kinases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 8.3.1.3 Adaptor Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 8.3.1.4 E3 Ubiquitin Ligases – Negative Regulation by Protein Endocytosis and Degradation . . . . . . . . . . . . . . . . . . . . . 234 8.3.2 Transmembrane Adaptors Modulating FcεRI Signaling . . . . . . . 236 8.3.2.1 Adaptor Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 8.3.2.2 Tetraspanins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 8.3.3 Modulation of the FcεRI Signaling Cascade by ITIM-Containing Receptors . . . . . . . . . . . . . . . . . . . . . 237 8.3.3.1 ITIM-Bearing Immunoglobulin-like Receptors . . . . . . . . . . . . 239 8.3.3.2 ITIM-Bearing C-Type Lectins. . . . . . . . . . . . . . . . . . . . . . 245 8.4 Epilogue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 CHAPTER 9 Histamine Receptors and Signaling . . . . . . . . . . . . . . . . . . . . . . 265 Hargita Hegyesi, Zsuzsa Darvas, Robin L. Thurmond, András Falus 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265 9.2 H1Receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 9.2.1 The H1 Receptor Signaling Pathway . . . . . . . . . . . . . . . . . . 266 9.2.2 Some Effects of Histamine Through H1Receptor. . . . . . . . . . . 269 9.3 H2Receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 9.3.1 The H2 Receptor Signaling Pathway . . . . . . . . . . . . . . . . . . 271 9.3.2 Some Effects of Histamine Through H2Receptor. . . . . . . . . . . 272 Contents XIII 9.3.3 H1 and H2 Receptors on Human Neoplasias. . . . . . . . . . . . . . 273 9.4 H3Receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 9.4.1 The H3 Receptor Signaling Pathway . . . . . . . . . . . . . . . . . . 275 9.4.2 Some Effects of Histamine Through H3Receptors . . . . . . . . . . 276 9.4.3 Uses of H3Receptor Antagonists . . . . . . . . . . . . . . . . . . . . 277 9.5 H4Receptor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 9.5.1 The H4 Receptor Signaling Pathway . . . . . . . . . . . . . . . . . . 279 9.5.2 Some Effects of Histamine Through H4Receptors . . . . . . . . . . 280 9.5.3 Uses of H4Receptor Antagonists . . . . . . . . . . . . . . . . . . . . 281 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 CHAPTER 10 Signal Transduction by Ion Channels in Lymphocytes . . . . . . . . . . . 293 Zoltán Varga, Rezs´o´ Gáspár 10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 10.2 The Role of Ion Channels in T Cell Activation . . . . . . . . . . . . 293 10.2.1 Ca2+ Release-Activated Ca2+ (CRAC) Channels . . . . . . . . . . . . 296 10.2.2 Voltage-Gated and Ca2+-Activated K+ Channels. . . . . . . . . . . . 297 10.2.3 Ion Channels,Membrane Potential and Lymphocyte Activation. . . . . . . . . . . . . . . . . . . . . . . 299 10.2.4 Distribution of Kv1.3 Channels in the Lymphocyte Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 10.3 The Role of Ion Channels in Volume Regulation by Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 10.4 The Role of Ion Channels in the Apoptosis of Lymphocytes. . . . . 305 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307