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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signal transduction FCG RECEPTOR SIGNALING TÁMOP-4.1.2-08/1/A-2009-0011 Types of human Fc receptors Activating Fc Receptors FcRI FcRIIA FcRIIC FcRIIIA Inhibitory Fc Receptor FcRIIIB Human N 2 N N N N FcRIIB N N 2 N N N GPI C C ITAM C C Affinity Alleles ITIM C C C High C C Low-medium FcRIIA131H FcRIIA131R Low-medium C Low-medium FcRIIIA158V FcRIIIA158F Low-medium Low-medium FcRIIB232I FcRIIB232T TÁMOP-4.1.2-08/1/A-2009-0011 Mouse Fcgamma receptors Activating Fc Receptors FcRI FcRII Inhibitory Fc Receptor FcRIV FcRIIB Mouse N N 2 N 2 N C N N 2 N C N N ITIM C ITAM C C Affinity N C High C C Low-medium C C Low-medium Low-medium TÁMOP-4.1.2-08/1/A-2009-0011 Role of ITAMs • ITAM is a specific sequence of amino acids (YXXL) occurring twice in close succession in the intracellular tail of a receptor. • After ligand binding, the tyrosine (Y) residue of the ITAM is phosphorylated by tyrosine kinases, and a signaling cascade is generated within the cell. • An ITAM is present in the intracellular tail of FcRIIA and C, and in the chains of FcRI and FcRIIIA. TÁMOP-4.1.2-08/1/A-2009-0011 Activatory Fc receptor signaling Immune complex FcRIII 2 Ca2+ 2 Plasma membrane PlP2 Cytoplasm PlP3 LYN PLC BTK P SYK ITAMs PI3K RAC DAG IP3 RHO PKC Ca2+ P SOS RAS Downstream signalling pathways (ERK, p38, JNK) Cytokine release Cell activation ADCC Phagocytosis Ca2+ ER Oxidative burst TÁMOP-4.1.2-08/1/A-2009-0011 Steps of Fc signaling 1 Src kinase-mediated tyrosine phosphorylation of the ITAMs 2 Following by SH2 domain-mediated recruitment of Syk family kinases to ITAMs 3 Activation of PI-3 kinase 4 Recruitment of adapter molecules like SLP-76 and BLNK 5 Recruitment of enzymes like phospholipase C and Tec family kinases 6 Generation of IP3 and DAG 7 Intracellular free Ca2+ mobilization TÁMOP-4.1.2-08/1/A-2009-0011 Inhibitory Fcγ receptor signaling Simultaneous cross-linking BCR FcRIIB PlP2 LYN ITIM P SHIP DOK Ig SHC PlP3 No membrane recruitment BTK Igβ RAS Inhibition of calcium flux and proliferation PLC TÁMOP-4.1.2-08/1/A-2009-0011 Inhibitory Fcγ receptor signaling Immune complex FcRIIB ITIM BTK JNK P cABL Apoptosis TÁMOP-4.1.2-08/1/A-2009-0011 ITIM • The presence of only one YXXL motif is not sufficient to activate cells, and represents a motif (I/VXXYXXL) known as an Immunoreceptor tyrosine-based inhibitory motif (ITIM) • FcγRIIB1 and FcγRIIB2 have an ITIM sequence and are inhibitory Fc receptors: they do not induce phagocytosis but counteract the antigen-induced BcR signal on B cells and shut off B cell activation • The inhibitory signal is controlled by SHP-1 and SHIP-phosphatases TÁMOP-4.1.2-08/1/A-2009-0011 Overview of Fcγ receptor signaling IgG Ag 2 FcRI FcRIIB FcRIIA 2 FcRIIIA Ca2+ CaCn P P P ITAM P ITIM PIP3 SYK P SYK P P SHIP P P P P Src Family PTKs SYK Co-ligation to Activation partner Ca2+ PI3K Rho family GTPases Src Family PTKs VAV P PYK2 IP3R SYK PLC RAS Actin polymerization and remodelling BTK BLNK DAG IP3 Ca2+ ER Calcium signali ng Phagocytosis Actin polymerization PKC RAC MAPK pathway Phagocytosis JNK Degranulation ADCC Cytokine release p38 Cell proliferation Proinflammatory responses Triggering agents and regulatory cytokines TÁMOP-4.1.2-08/1/A-2009-0011 Triggering agents and regulatory cytokines IL-5 IL-3 GM-CSF SCF IgE IgG IL-4 Bacteria and other TLR ligands TLR FcRI IL-5R IL-3R KIT FcR Eosinophil Basophil IL-4 Mast cell IL-5 and IL-13 IL-4R Monocyte/ macrophage Histamine Mediators produced by cells IL-1, IL-6 and TNF TÁMOP-4.1.2-08/1/A-2009-0011 Role of FcRs: enhanced phagocytosis IgG opsonized particle Ag IgG FcRIIA Src Family PTKs 2 P Src Family PTKs P P FcRI 2 P Src Family PTKs FcRIIIA P P P P ITAM P Phosphorylation of ITAMs P SYK PLC2 DAG IP3 PKC Ca2+ PI3K Actin polymerization and particle internalization TÁMOP-4.1.2-08/1/A-2009-0011 Role of FcRs: enhanced phagocytosis I Ag Pathogen IgG D2 Effector cell FcR 2 TÁMOP-4.1.2-08/1/A-2009-0011 Role of FcRs: enhanced phagocytosis II Fc receptor Antibody Microbe TÁMOP-4.1.2-08/1/A-2009-0011 ADCC Neutrophil Ab bound to Ag and Fc receptor NK cell Target cell Eosinophil Surface Ag Lytic enzymes Perforin Fc receptor TNF Granzymes Macrophage
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